Mouse models to interrogate the developmental pathogenesis of Huntington's disease

Abstract

Huntington's disease (HD) has traditionally been viewed as a late-onset neurodegenerative disorder. However, emerging evidence suggests that differences in the stoichiometry of wild-type huntingtin (HTT) and mutant huntingtin (mHTT) exert a complex spectrum of pathogenic effects during early brain development, preceding the onset of overt clinical signs by several decades. In this review, we examine how various HD mouse models have revealed distinct yet frequently converging developmental abnormalities through the dynamic interplay of novel early pathogenic and homeostatic processes. Full-length transgenic models like BACHD demonstrate early glial dysmaturation, corticostriatal synaptic deficits, and behavioral phenotypes emerging during infancy. Truncated fragment models such as R6/2 exhibit aggressive phenotypes resembling juvenile HD, with early neuronal and myelination defects. Knock-in models, including HdhQ111, HdhQ140, and zQ175, highlight CAG-length-dependent disruptions in neural progenitor cell dynamics, synaptic formation, and cortical plasticity. Loss-of-function models further implicate wild-type HTT in neural patterning and germ layer specification, recapitulating HD-like features in the absence of mHTT overexpression. Together, these models underscore a developmental dimension to HD pathogenesis and suggest that early-life circuit miswiring, glial dysfunction, and impaired integrity of the specification, maturation, and maintenance of neural cell identity and functions may prime the brain for later neurodegeneration. Understanding these early disruptions is essential for identifying novel early therapeutic windows, biomarkers, and molecular targets essential for devising true disease-modifying paradigms aimed at delaying, reversing, or even preventing the onset of disease hallmarks.

Plain language summary abstract

Huntington's disease (HD) is a neurological disease that causes progressive motor, cognitive, and psychiatric symptoms in adulthood. However, growing evidence indicates that HD-related changes in the brain begin much earlier, long before clinical symptoms emerge. This review explores how different genetically modified mouse models have helped us better understand and conceptualize these early changes. These models reveal that HD can impair the development and function of neurons and glial cells, disrupt synaptic connections, and alter the formation of key brain circuits involved in movement, emotion, and cognition. By investigating these developmental disruptions, researchers aim to identify critical periods for intervention and to discover new strategies for preventing or delaying disease onset. This developmental perspective offers new opportunities to reshape how we understand and treat HD.

Keywords

Huntington’s disease developmental pathogenesis mouse models huntingtin neurogenesis

Introduction

Huntington's disease (HD) has historically been viewed as a late-onset neurodegenerative disorder, with progressive motor, cognitive and psychiatric deterioration typically beginning in mid-to-adult life.^1,2 However, this adult-onset framing may obscure earlier, developmentally mediated disease processes. Increasing evidence indicates that alterations in neuronal integrity and function emerge long before symptom onset, reflecting early disturbances in developmental processes including but not limited to stress responses, neuroinflammation, and circuit maturation.^3–8 Indeed, the expanded CAG repeat in the huntingtin gene (HTT) affects not only neuronal survival in adulthood but also fate specification, progenitor behavior, and circuit assembly during early development^9,10 prompting a broader, lifespan-based view of HD with potential implications for early intervention.¹¹

Neuroimaging studies in premanifest HD gene carriers including children and adolescents have identified early structural abnormalities such as altered cortical thickness, reduced striatal volume, delayed white matter maturation, and disrupted connectivity, many emerging years or even decades before symptom onset.^12–15 Notably, neuroimaging and transcriptomic investigations have shown that cortical regions displaying early structural alterations correspond to regions enriched for neurodevelopmental gene expression programs, suggesting that regions dependent on HTT-mediated developmental processes may become selectively vulnerable later in life.⁶ However, human studies are inherently limited in their capacity to dissect mechanism from consequence, to manipulate specific variables, or to examine developmental trajectories at the cellular, molecular and biophysical levels.

Animal models provide the experimental leverage to address these limitations. Transgenic models such as BACHD and R6/2 reveal early abnormalities in neuronal differentiation, corticostriatal synapse formation and glial maturation well before evidence of cell death.^15,16 Knock-in (KI) models, including HdhQ111, HdhQ140, and zQ175, preserve endogenous regulatory control of Htt expression, demonstrate early disruptions in cell cycle dynamics, cortical laminar organization, and synaptic plasticity during embryonic and early postnatal periods. Loss-of-function (LOF) models further establish that HTT plays essential roles in embryonic stem cell maintenance, germ layer specification, body axis patterning, neural induction, and neural progenitor cell self-renewal, with perturbation producing structural and functional abnormalities relevant to HD.¹⁷

Importantly, these models illuminate a fundamental mechanistic distinction. In dividing neural progenitors, HTT is required for mitotic spindle orientation, fate specification, and intracellular trafficking,^18–21 functions disrupted by mHTT independently of the somatic expansion-driven transcriptional toxicity that emerges in mature neurons.^22–25 While mouse models employing CAG expansions exceeding 100 repeats do not recapitulate the same clinical profiles and severity of human juvenile HD (such as early lethality, seizures, and rapid progression),^26,27 they reveal that the contributions of developmental impairments reflect the degree of HTT functional compromise, whether through truncation, expansion, or gene loss, rather than CAG length alone.^22,28–31

Convergent evidence from animal models, human fetal tissues, and premanifest neuroimaging studies supports that developmental alterations occur in HD mutation carriers.^32–35 Together, these observations support a two-component model of HD pathogenesis: early mHTT disrupts HTT-dependent developmental processes, establishing latent vulnerabilities,^33–35 while progressive somatic expansion in adulthood crosses transcriptional thresholds that trigger overt degeneration.^23,36,37 This framework explains both early developmental differences in premanifest carriers and the later circuit-selective degenerative patterns despite ubiquitous HTT expression.^38,39

In this review, we compare major classes of HD mouse models, transgenic, KI, and LOF, to examine how each illuminates the developmental origins of HD pathology. Table 1 provides a comparative overview of the most commonly used HD mouse models, highlighting genetic constructs, CAG repeat length, and key developmental phenotypes. By integrating molecular, cellular, biophysical, and circuit-level findings across models, we aim to clarify how early developmental defects shape disease vulnerability and to frame the key questions that must be addressed to identify critical windows for therapeutic intervention. What emerges is not merely a catalog of early abnormalities, but a true conceptual reframing: the adult neurodegenerative phenotype may be the final act of a trajectory that begins in the developing brain.

Transgenic mouse models

The BACHD mouse model stands out as a prevailing tool in HD research due to its incorporation of the full-length human mutant huntingtin (mHTT) gene, including all exons, introns, and regulatory elements, driven by the native human HTT promoter. This genomic construct ensures physiologically relevant expression patterns across various tissues and developmental stages, capturing potential human-specific regulatory features absent in KI models that humanize only the coding region of exon 1. Notably, BACHD mice exhibit robust HD-like phenotypes with approximately 97 CAG repeats, a lower count than some KI models like zQ175, which harbor over 140 repeats.^27,40,41 This suggests that factors beyond polyglutamine length, such as the inclusion of untranslated regions (UTRs) and intronic sequences, may influence disease manifestations. In KI models, the lack of the 5′ UTR in exon 1 could omit key regulatory elements that contribute to RNA toxicity. Emerging evidence indicates that expanded CAG repeats can form stable hairpin structures in RNA, leading to the sequestration of RNA-binding proteins and subsequent splicing alterations, thereby contributing to pathogenesis.⁴² Furthermore, the BACHD model's design includes loxP sites flanking exon 1, enabling Cre recombinase-mediated, cell type- and temporally specific excision of mHTT. This feature allows researchers to dissect the contributions of mHTT expression in specific cell populations, such as neurons or glial cells, and at distinct developmental stages, providing insights into the cell-autonomous and non-autonomous mechanisms underlying HD pathology.⁴⁰ In summary, the BACHD mouse model's comprehensive genomic representation of the human HTT gene, combined with its robust phenotypic expression and genetic manipulability, makes it an invaluable resource for elucidating the complex molecular and cellular mechanisms of Huntington's disease.

A critical mechanistic contrast emerges when comparing full-length transgenic models such as BACHD with truncated exon-1 models like R6/2.^30,40 R6/2 mice express only the N-terminal fragment of mHTT, which likely lacks the functional domains required for HTT's developmental roles and may exert dominant-negative effects on the remaining wild-type allele.^10,43 This dual insult (loss of wild-type HTT function combined with fragment-mediated toxicity) disrupts essential HTT-dependent processes, including mitotic spindle organization and early neuronal maturation.^18,19 Accordingly, R6/2 mice exhibit rapid disease progression and premature lethality despite possessing CAG expansions comparable to or greater than those of full-length models.³⁰ Notably, Morton et al. demonstrated that R6/2 mice carrying approximately 50 CAG repeats show no deleterious behavioral effects despite eventually developing aggregate pathology, strongly suggesting that the aggressive R6/2 phenotype arises from LOF and dominant-negative mechanisms rather than CAG length alone.⁴⁴ In contrast, even with high repeat lengths, full-length constructs retain sufficient protein architecture to support embryonic viability and early postnatal development.^40,45 This divergence underscores that developmental severity in HD models may reflect the degree of HTT functional compromise whether through fragment expression, dominant-negative interference, or outright HTT loss.⁴⁶

One particularly notable developmental phenotype in BACHD mice is compromised myelination. Beginning during early postnatal life, white matter abnormalities feature prominently, especially within the corpus callosum and striatum. Ultrastructural studies have identified both transcriptional dysregulation of myelin-related genes and structural alterations such as elevated G-ratios indicating thinner myelin sheaths and disrupted lamellar organization.^41,47 These findings complement white matter changes observed in preclinical HD patients.^47–50 Research by Xiang et al. has revealed significant reductions in myelin basic protein (MBP) expression and downregulation in the synthesis of cholesterol genes by postnatal day (P) 14, correlating with reduced oligodendrocyte function due, in part, to PGC-1α repression.¹³ Subsequent work by Bardile et al. confirmed that these defects are evident within the first month of life and are epigenetically mediated by upregulated activity of the polycomb repressive complex 2, which silences key myelin genes such as MBP and myelin oligodendrocyte glycoprotein (MOG).⁵¹

In addition to oligodendrocyte-related abnormalities, early glial dysfunction in HD extends to astrocytes and microglia, both of which show early morphological and transcriptional changes, as detailed in subsequent sections.^52–59 Critically, both cell types play essential developmental roles, astrocytes regulate synapse formation and maturation,^60,61 while microglia mediate activity-dependent synaptic pruning during critical periods,^55,62–64 raising the possibility that their early dysfunction contributes to circuit miswiring in HD. Complementing these glial disturbances, neural stem cells isolated at E13.5 display reduced proliferation and generate fewer MAP2 + neurons and CNPase + oligodendrocytes after seven days in vitro.⁶⁵ These results suggest that mHTT can interfere with early neural lineage specification during brain development.

These developmental anomalies give rise to early behavioral impairments. Before any overt motor signs emerge, BACHD pups exhibit altered behaviors such as changes in ultrasonic vocalizations by P10 and increased risk-taking behavior by P21. These early phenotypes are likely associated with epigenetic dysregulation of neural developmental genes and are partially reversible with histone deacetylase inhibitor administration.⁶⁵ Lundh et al. found these behavioral changes persist and intensify by two months of age, including signs of anxiety and depression. These are accompanied by molecular dysregulation of the hypothalamus, including reduced neuropeptide Y and vesicular monoamine transporter type 2 expression, and conversely increased cocaine and amphetamine regulation of corresponding transcript expression. Interestingly, although the number of orexin-expressing neurons increases, their somal sizes decrease, suggesting compensatory but maladaptive cellular and molecular feature shifts.⁶⁶

Underlying many of these behavioral outcomes are fundamental synaptic defects within corticostriatal pathways. Electrophysiological recordings and immunostaining of BACHD neurons during the third to fifth weeks in vitro reflect diminished synapse formation and impaired connectivity. Gu et al. have demonstrated that such deficits can be reversed with exogenous brain-derived neurotrophic factor (BDNF).⁶⁷

Astrocyte-mediated dysfunction also plays a central role in early pathogenesis.^68–70 These glial cells are crucial for clearing glutamate via excitatory amino acid transporters to prevent excitotoxicity.^71,72 However, mHTT-expressing astrocytes show compromised glutamate uptake, across various HD models, contributing to neuronal vulnerability.^69,73,74 In BACHD mice, Wood et al. have shown that targeted reduction of mHTT in astrocytes from P22 to P32 via GFAP-CreERT2 and tamoxifen exposure significantly protects against behavioral, neuropathological and electrophysiological changes. This intervention also restored the levels of αB-crystallin, a small heat shock protein involved in cellular stress responses, in the striatum, suggesting the active role of astrocytes in homeostasis and disease progression.⁷⁵

Employing the BACHD model, Molero et al. demonstrated that postnatal inactivation of mHTT after P21 via tamoxifen-inducible CreERT2 failed to fully rescue key pathological features of the disease. Despite successful genetic silencing of mHTT expression after the completion of all developmental milestones, mice continued to exhibit motor abnormalities, persistent synaptic deficits within corticostriatal circuits, and ongoing cortical and striatal dysfunction. These findings strongly suggest that critical pathogenic processes are initiated during early neurogenesis, prior to P21, and may become essentially irreversible by the time mHTT is suppressed.⁷⁶ Further emphasizing the role of developmental mechanisms in HD, Soylu-Kucharz et al. demonstrated that genetic deletion of mHTT via Sim1-Cre, which is active in hypothalamic progenitors beginning at E10.5, prevents the development of HD-associated metabolic and mood phenotypes.⁷⁷ Because recombination occurs during embryonic development, mHTT is removed before it can disrupt hypothalamic circuit formation, constituting developmental prevention rather than postnatal reversal and underscoring the critical importance of early developmental windows. Consistent with these findings, Cheong et al. revealed that early, global inactivation of mHTT in the central nervous system via Nestin-Cre improves motor coordination, mood-related behaviors, and metabolic outcomes. In contrast, targeted inactivation in dopamine (D2) receptor-expressing medium spiny neurons (MSNs) using A_2A-Cre failed to yield significant improvements, despite effectively lowering mHTT expression in these cells.⁷⁸ This discrepancy likely reflects two key factors: first, A_2A-Cre recombinase activity begins later, whereas Nestin-Cre is active during embryonic development, potentially bypassing a critical embryonic or early-postnatal window during which m initiates developmental disruptions; and second, m-mediated toxicity is not strictly cell-autonomous: D2 MSNs remain vulnerable due to persistent dysfunction in surrounding glial or cortical inputs that continue to express m.^79,80 Together, these studies underscore that both developmental timing and network-wide m expression determine therapeutic efficacy.

In contrast to the full-length BACHD model, the R6 murine lines (R6/1 and R6/2) represent truncated transgenic constructs expressing only exon 1 of the human HTT gene with expanded CAG repeats, approximately 115 in R6/1 and 150 in R6/2 mice, respectively. Originally developed by Mangiarini et al., these models express N-terminal fragments of mutant huntingtin.³⁰ Both R6/1 and R6/2 mice exhibit a remarkably rapid disease progression, with early-onset behavioral and motor deficits, weight loss, and seizures.^81–83 The mechanisms underlying this severity, including fragment aggregation, LOF, and dominant-negative effects, are discussed above.^82,84,85 In R6/2 mice, these symptoms typically emerge by 8–12 weeks of age and lead to premature death by 13–16 weeks.^81–83 By contrast, compared to R6/2 mice, R6/1 mice display delayed onset, slower progression, and extended life span, with motor impairments often developing between 13–20 weeks of age.⁸² These features parallel certain aspects of juvenile-onset Huntington's disease, a disorder showing a plethora of neurological alterations likely reflecting underlying neural developmental deficits. This makes the R6/2 model especially valuable for investigating early, severe HD phenotypes.³⁰

Consistently, several studies have demonstrated developmental impairments in R6/1 and R6/2 lines, including: deficits in hippocampal neurogenesis,^86–88 early disruption of the thalamocortical circuit,^89–91 disorganization of cortical layers reminiscent of focal cortical dysplasias, morphological changes on cortical pyramidal neurons, including dystrophic neurites, as well as tortuosity and misorientation of neuronal processes.⁹² Other studies have shown loss of cell identity markers in cortical interneurons, that may well underlie the developmental misspecification of this lineage.⁹³ Furthermore, Cepeda et al. found important changes in passive and active membrane properties of cortical pyramidal and medium spiny neurons that are suggestive of delayed neuronal development.⁹²

Despite these profound deficits, a series of studies progressively established a regenerative context for HD based on the induction of striatal neurogenesis through application of BDNF, a key promoter of neuronal survival and plasticity, and Noggin, an antagonist of BMP signaling that fosters neural differentiation.^94–96 Cho et al. demonstrated that adenoviral-mediated overexpression of BDNF and Noggin in R6/2 mice promoted recruitment of subependymal progenitors (neural stem-like cells residing in the adult subventricular zone) into the neostriatum, generating DARPP-32+ MSNs that modestly improved motor function and extended survival.⁹⁴ Benraiss et al. refined this approach using AAV4 vectors to drive sustained transgenic growth factor signal expression within the ependymal lining (which interfaces with the subventricular zone niche), resulting in robust generation of electrophysiologically mature MSNs with both direct (substance P+) and indirect (enkephalin+) pathway phenotypes, leading to significant functional rescue.⁹⁵ Cano et al. further validated the strategy by integrating fate mapping, monosynaptic rabies tracing, in vivo calcium imaging, and chemogenetics to demonstrate that the newly generated, functionally mature MSNs not only reconstitute cortico-striato-pallidal connectivity but also actively modulate motor behavior. Together, these studies provide compelling evidence that endogenous neural progenitor-driven striatal neuron replacement can achieve structural, functional, and behavioral restoration in even severe models like those of R6/2 mice.

Developmental impairments are not only restricted to neurons. Recent work by Benraiss et al. further highlights the extent of developmental impairments in R6/2 mice by demonstrating a progressive failure in callosal myelination and a marked delay in remyelination after induced demyelination. Their study identified a cell-intrinsic defect in oligodendrocyte progenitor cell (OPC) differentiation linked to repressed TCF7L2 signaling, occurring at a key developmental nexus associated with the pre-ensheathing phase of incipient oligodendrocyte myelination. Notably, overexpression of TCF7L2 in vivo was sufficient to restore myelin gene expression and remyelination capacity in R6/2 mice, underscoring a key regulatory pathway disrupted in HD glia and reinforcing the notion that non-neuronal cell types and their developmental signaling pathways also contribute significantly to the HD phenotype.⁹⁷

While R6 models have provided valuable insights into gain-of-function toxicity driven by N-terminal mHTT fragments, they also raise critical questions regarding the role of wild-type HTT loss in driving developmental abnormalities. In support of the LOF contributions, mouse models with targeted loss of HTT replicate key HD-like phenotypes, and genetic complementation studies have shown that reintroduction of full-length HTT can partially rescue developmental defects in embryonic stem cell-derived lineages.^98–100 It is therefore plausible that LOF mechanisms are disproportionately represented in the R6/1 and R6/2 models, contributing to the severity of developmental abnormalities observed in these mouse models.

Loss-of-function mouse models

Accumulating evidence suggests pathogenic developmental components are preferentially associated with LOF mechanisms.^101,102 Animal and cellular models in which HTT is reduced or ablated have revealed key developmental abnormalities.^{15,25,29,103–107}

The LOF effects arise from huntingtin's diverse physiological roles during neurogenesis including mitotic spindle organization, nuclear translocation, and intracellular trafficking which are mechanistically distinct from the transcriptional dysregulation that is thought to drive adult neurodegeneration.²³ Among these functions, huntingtin acts as a scaffold for mitotic spindle assembly and orientation in dividing neural progenitors, while also facilitating nuclear translocation of key signaling molecules and maintaining trophic support. Work by Godin et al., Keryer et al. and others demonstrates that mHTT expression disrupts spindle pole formation, alters orientation angles, prolongs mitotic checkpoints, and shifts the balance of symmetric versus asymmetric division.^18,19,21 These post-translational and structural disruptions operate independently of the transcriptional toxicity pathway that emerges in postmitotic neurons.^24,33 The resulting alterations in lineage composition and early circuit assembly likely contribute to latent vulnerabilities that shape later-life degeneration.^6,108

Ablation of HTT has revealed that this protein has essential roles during embryogenesis. The first demonstration of this came from Zeitlin et al., who generated homozygous Htt-null mice and observed that embryos died between embryonic day (E) 7.5 and 10.5 due to profound developmental failure.¹⁵ Dragatsis et al. extended these findings by showing that knock-out embryos failed to undergo proper gastrulation, with defects in extraembryonic tissues, germ layer formation, and neural tube closure.^109,110 Nguyen et al. used an in vitro murine embryonic stem cell system to overcome early lethality, showing that is HTT required for proper specification of all three cardinal germ layers and associated somatic lineages by disrupting pluripotency network signaling pathways critical for stem cell commitment and regional identity.^17,110 These abnormalities in LOF models parallel phenotypes seen in HD patient-derived lines, suggesting a shared pool of transcriptional and epigenetic vulnerabilities.^111–114

Conversely, Auerbach et al. developed a hypomorphic mouse model expressing reduced levels of HTT to investigate the consequences of partial LOF effects.¹¹⁵ These mice displayed a range of neural developmental abnormalities, including forebrain heterotopias, impaired neuronal migration, defective neurogenesis, and early disruptions in neural lineage specification and regional brain organization.¹¹⁶ Notably, the presence of heterotopias was later corroborated in postmortem studies of human HD brains,¹¹⁷ suggesting its translational relevance. In addition to structural abnormalities, Auerbach's model demonstrated that mice expressing low levels of mutant huntingtin (Q111) developed a progressive and ultimately lethal neurological disorder. Early phenotypes emerged by 3–4 months of age and included hindlimb clasping during tail suspension, tail stiffness, and subtle gait abnormalities. As the disease progressed, mice exhibited reduced left-right hindlimb alternation (“hopping” gait), limb stiffness or paralysis, resting tremors, seizure-like episodes, and difficulties initiating movement after handling. By 12 months, most mice developed severe hypokinesia or full paralysis, leading to premature death. This demonstrates that reduced HTT expression during development produces long-lasting functional consequences.

Since HTT was continuously expressed at low levels throughout development and adulthood in the hypomorphic model, it remained unclear whether these behavioral defects reflected strictly developmental roles or a combination of developmental and later postnatal influences. This limitation was addressed by Molero et al. through rescuing the hypomorphic expression in pubescent mice via excisional recombination. Despite normalization of HTT expression throughout the rest of the postnatal life, the animals still displayed behavioral abnormalities, seizures and persistent basal ganglia degeneration, indicating these HD-like phenotypes represented the consequences of LOF mechanisms operating during neural development.^76,116

In a subsequent study, Mehler et al. selectively ablated HTT in two complementary domains within the ventral telencephalon giving rise to the basal ganglia: the Gsx2- and the Nkx2-domains. The former domain gives rise to MSNs and globus pallidus arkypallidal cells while the latter to interneurons and globus pallidus prototypical cells. Both conditional KO models displayed a plethora of HD-like phenotypes, including hyperkinetic motoric phenotypes, age-dependent motor coordination deficits, weight loss, and basal ganglia degeneration. Interestingly, these models also displayed interneuron deficits, a trait also described in HD cases.¹¹⁸

Collectively, these findings establish that LOF mechanisms produce developmental abnormalities with lasting HD-like consequences, making LOF strains an important alternative for dissecting developmental contributions to HD pathogenesis.

Knock-in mouse models

While transgenic models such as BACHD and R6/2 have been indispensable in understanding Huntington's disease pathogenesis, each comes with notable limitations. BACHD and YAC128 mice carry full-length human HTT transgenes but exist outside the endogenous mouse Htt genomic locus, which can lead to copy number effects and ectopic expression patterns. Furthermore, these models often express mHTT at supraphysiologic levels, potentially distorting disease mechanisms and impeding the translation of preclinical findings. To address these issues, KI models were developed. These mice retain the native mouse Htt promoter and regulatory context but introduce a humanized exon 1 with expanded CAG repeats into the mouse endogenous Htt gene locus. This approach ensures endogenous-level expression of mHTT, enabling a more physiological model of HD with accurate spatial, temporal, and developmental control. Additionally, KI models preserve downstream introns and exons, allowing for investigation into full-length mHTT processing, somatic instability, and the generation of toxic N-terminal fragments.

Moderate-CAG KI models (Q50-Q80, including HdhQ80 and newly developed Q50 variants) present an instructive contrast to higher-expansion lines. Comprehensive phenotypic characterization by Langfelder et al. across an allelic series (Q20 through Q175) demonstrated CAG length-dependent emergence of transcriptional, behavioral, and neuropathological changes in adult animals, with Q50 and Q80 lines showing minimal overt abnormalities on standard assessments.¹¹⁹ However, existing characterizations have focused almost exclusively on adult endpoints; developmental phenotypes in these moderate-expansion models remain largely unexplored.^{18,108,120,121} This represents a significant gap, as human neuroimaging studies demonstrate that adult-onset carriers exhibit subtle but measurable developmental trajectory differences.^34,35 These models primarily manifest pathology during adulthood through cumulative cellular stress and somatic expansion.^122,123 Recent work from Handsaker et al. demonstrates that somatic CAG expansion must exceed approximately 150 repeats before transcriptomic dysregulation emerges in adult neurons, consistent with a distinct, later-acting degenerative mechanism.²³

A unique aspect of their creation involved leveraging the phenomenon of CAG repeat instability, also known as anticipation, where expanded repeats naturally lengthen over successive generations.¹²⁴ Researchers used this spontaneous somatic instability to establish mouse lines with ever increasing CAG lengths from approximately 111 (HdhQ111) to 140–150 (HdhQ140/150) and eventually to 250 (HdhQ250). These incremental expansions have allowed the modeling of a phenotypic continuum, with longer repeats generally producing more severe disease states and/or earlier developmental abnormalities.^124,125 The zQ175 model, in contrast, results from a targeted insertion of ∼190 CAG repeats into exon 1 of the Htt gene and serves as a widely used intermediate-severity model.^27,126 Together, these KI models form a spectrum that parallels human genotype-phenotype correlations and enables high-fidelity exploration of early disease mechanisms.

At the embryonic level, HdhQ111 mice exhibit a suite of neural developmental abnormalities. Analyses during peak striatal neurogenesis (E13.5- E14.5) have revealed delays in subpallial progenitor maturation, characterized by abnormal spatiotemporal proliferation profiles and disrupted cell cycle exit. While the persistence of these cellular-level proliferation defects into adulthood has not been directly assessed in KI models, evidence from the R6/2 model demonstrates that early developmental circuit abnormalities, including delayed cortical maturation and aberrant synaptic connectivity, establish permanent functional deficits in corticostriatal excitation/inhibition balance and circuit hyperexcitability that persist into symptomatic stages, even as many intrinsic membrane properties normalize.^{92,121,127,128} Clonal expansion assays have confirmed that neural progenitors from these embryos possess reduced proliferative capacity and deviate from typical differentiation trajectories.¹⁰⁸ Conversely, cortical studies using Q111 cell lines identify misorientation of mitotic spindles in neural progenitors (E10.5-E14.5), resulting in thinner ventricular zones, thicker cortical plates and altered lamination patterns without increased apoptosis.^18,19 Remarkably, Akt-mediated phosphorylation of mHTT can rescue these defects, linking molecular signaling to cortical architecture.¹⁹

A key downstream consequence of these early defects is impaired formation of the corticostriatal pathway, a critical excitatory projection from cortical pyramidal neurons (primarily layers II/III and V) to striatal MSNs. Normally, this pathway develops through a sequence of temporally regulated steps, including cortical and striatal neurogenesis, guided axonal extension through the internal capsule, and activity-dependent synaptogenesis during the late embryonic and early postnatal period.^129,130 By the first postnatal week, cortical axons form glutamatergic synapses onto MSNs, enabling sensorimotor circuit function.¹³¹ However, in HdhQ111 mice, excitatory synaptic activity in cortical layers II/III is diminished during this critical window, with fewer glutamate receptors and early sensorimotor abnormalities. These early deficits, which are reversible with ampakine treatment, suggest a brief developmental window during which cortical circuits are particularly vulnerable and potentially modifiable. Though these changes self-correct morphologically, functional deficits persist into adulthood unless rescued pharmacologically.¹³¹ More pronounced cortical synaptic abnormalities are evident in HdhQ140 mice, where impaired long-term potentiation in the hippocampus is linked to defective actin polymerization in dendritic spines and reduced BDNF signaling.¹³² These impairments can be reversed with pharmacologic enhancement of BDNF signaling, further underscoring the plastic nature of these early deficits. The zQ175 model expands on these findings by showing excessive formation of excitatory cortical and thalamocortical synapses by P21, followed by premature pruning and loss of dendritic spines.¹³³ This sequence suggests a dysregulated refinement of cortical connectivity that mirrors the patterns seen in human HD carriers.

Glial dysfunction is a prominent and early feature in KI models of HD, implicating non-neuronal mechanisms in the developmental trajectory of pathology. Myelination deficits emerge across multiple KI lines, even in the presence of normal oligodendrocyte counts. In HdhQ140 mice, myelin-associated proteins including MBP, MAG, MOG, and CNP are markedly reduced in the striatum and prefrontal cortex, despite preserved transcriptional profiles.¹³⁴ This pattern suggests defects in post-transcriptional regulation or intracellular trafficking that impair white matter maturation during development. zQ175 mice similarly show profound glial and myelin-related abnormalities: by 3 weeks of age, white matter regions such as the striatum and globus pallidus exhibit early hypertrophy followed by regression, accompanied by significant downregulation of MBP and MOG.¹³⁵ The HdhQ250 model, engineered with even longer CAG repeats, amplifies these phenotypes. By P14, these mice exhibit severely reduced expression of MOG, MBP, and the oligodendrocyte maturation factor MRF, as well as decreased numbers of mature CC1 + oligodendrocytes and fewer myelinated axons within the corpus callosum.^135,136 These findings demonstrate a CAG dose-dependent disruption of oligodendrocyte function and axonal ensheathment that manifests early in the postnatal brain.

Astrocyte abnormalities are also consistently observed across KI models. In HdhQ140, astrocyte-specific vesicular release of BDNF is impaired due to Rab3a-dependent docking failure of dense-core vesicles, compromising neurotrophic support during critical windows of synaptic maturation.¹³⁷ Together with the oligodendrocyte deficits described above, these findings indicate that glial dysfunction is an early and integral component of HD developmental pathogenesis.¹⁷

Integrative perspective on neural development and neurodegeneration

The findings across transgenic, KI, and LOF models converge on a fundamental reconceptualization of HD pathogenesis. Three decades ago, Mehler et al. postulated that neurodegenerative diseases represent primary disorders of neural development in which pervasive but subthreshold impairments in the trajectories of neural induction and progressive sculpting of the nervous system create unique disease-selective vulnerabilities and resilience profiles during a relatively silent but dynamic presymptomatic phase.^138,139 Emerging evidence has since revealed that multiple neurodegenerative disorders exhibit age-associated loss of terminal neuronal and non-neuronal cell identity and functional integrity, including dedifferentiation programs frequently associated with somatic stress responses.^23,140–149 Intriguingly, Molero et al. identified latent pluripotency molecules and programs embedded in evolving pathways of regional neurogenesis and neuronal subtype specification in HD mouse models.^{17,76,108,110} These observations have the potential to unify two complementary biological mechanisms: developmental perturbations that disrupt the fidelity of neurogenesis and neural network formation, and the long-term maintenance of regional neuronal and non-neuronal subtype identity.^34,36,150 Through this perspective, neurodegeneration may result not solely from pathological cell death, but from late-life deregulation of molecular and cellular programs whose vulnerabilities were established during development, a framework suggesting that therapeutic strategies targeting early prodromal periods, when these programs remain modifiable, may prove most effective.^35,65,151 This reframes HD not as a disease of midlife neuronal death, but as a lifelong continuum in which developmental and degenerative processes are inextricably linked. Testing this framework and translating it into therapeutic strategy requires addressing several key questions.

Future directions

The evidence reviewed in our manuscript supports an emerging model in which Huntington's disease pathogenesis involves two temporally and mechanistically distinct pathogenic components.^32,36 In the first pathogenic component, germline CAG expansion disrupts huntingtin's physiological roles during neurodevelopment, affecting mitotic spindle orientation, neuronal fate specification, and circuit assembly, producing subtle but consequential alterations in corticostriatal organization.^{18,19,33,108,133} Human neuroimaging studies confirm that these developmental differences are detectable in children and adolescents carrying the HD mutation.^34,35,127 In the second component, progressive somatic CAG expansion in post-mitotic neurons then triggers the cellular dysfunction and selective degeneration characteristic of manifest disease.^23,37

This two-component model has important implications for therapeutic strategy. If developmental alterations establish the regional vulnerability patterns that determine which circuits later degenerate, as suggested by recent neuroimaging-transcriptomic integration studies,⁶ interventions aimed solely at adult-onset mechanisms may be insufficient. Conversely, if these developmental and degenerative components are partially independent, therapeutic efforts could target the phase most amenable to modification. Determining this relationship will require approaches that move beyond descriptive phenotyping toward causal, mechanism-based dissection.

A key translational question is whether developmental vulnerabilities contribute to adult disease in ways that remain therapeutically accessible during prodromal phases. If developmental deficits create durable circuit-level abnormalities that persist into adulthood, this would motivate biomarker development to identify at-risk individuals when interventions may still be feasible.^18,33 Mouse findings can be extended using human iPSC-derived neural cultures and organoids, which recapitulate key developmental features of HD and permit mechanistic studies in human genetic backgrounds.^133,152,153 Mouse genetics remains well suited for dissecting cell-type-specific developmental mechanisms that can guide human studies.

A central unresolved challenge is whether early cellular abnormalities in HD reflect a developmental hierarchy (with dysfunction in one lineage driving others) or combinatorial effects of mHTT acting independently across cell types. Multiple lineages including cortical interneurons, pyramidal neurons, and striatal medium spiny neurons exhibit early dysfunction in HD models, yet it remains unclear whether one lineage initiates pathology, whether several are concurrently affected by germline CAG expansion, or whether multiple lineages act synergistically to produce early dysfunction.^18,33,133 Because these neuronal classes tightly co-regulate each other's maturation through reciprocal trophic and synaptic interactions, perturbations impacting individual lineages may propagate across cortical, striatal, and thalamic circuits, creating cascading effects that obscure causal origins.^152,153 Resolving these hierarchies requires lineage-specific manipulations that isolate intrinsic defects from network-dependent effects. LOF models offer an especially powerful strategy for clarifying these lineage-specific developmental requirements.^15,29,105 By selectively reducing or eliminating wild-type HTT in defined progenitor, precursor, or neuronal populations, LOF studies remove the confounding variability introduced by CAG-length-dependent toxic gain-of-function mechanisms. These models can reveal which developmental processes absolutely require huntingtin and which phenotypes arise secondarily from circuit-level disruption.^19,120 Such insights are essential for determining whether abnormalities in interneurons, MSNs, hypothalamic cells, or glia reflect intrinsic developmental dependencies or downstream network effects.

Defining the factors that render specific neuronal populations selectively vulnerable in HD is critical for generating early-stage therapeutic targets. Although current treatments focus primarily on adult stressors such as proteotoxicity and metabolic failure, developmental events may program which circuits ultimately deteriorate.^154,155 If early-life alterations in interneuron maturation, corticostriatal connectivity, or hypothalamic development shape later susceptibility, then identifying and correcting these early vulnerabilities could profoundly alter disease course. As illustrated by Braz et al., early circuit-level interventions can substantially delay onset and progression,¹³¹ highlighting the transformative potential of therapeutics targeting developmental origins of vulnerability.

A major gap in the field is the absence of molecular and lineage-level characterization of neural progenitor cells during embryonic and early postnatal neurogenesis in HD mouse models. Recent studies defining somatic expansion kinetics and transcriptional thresholds in adult neurons cannot be extrapolated to proliferating progenitors, which operate under different molecular constraints and exhibit CAG-dependent vulnerabilities through HTT's diverse developmental roles. Applying single-cell multi-omics, lineage tracing, and live imaging during early development will be essential for clarifying how these germline and somatic mechanisms interact across life.

To address questions most relevant to clinical translation, inducible mouse models incorporating lineage mapping capabilities must overcome current limitations in dissecting cell type-specific, temporal, and non-cell-autonomous mechanisms in HD. A critical priority is the development of conditional and inducible full-length human mHTT models under native regulatory control.⁴⁶ Such systems will enable precise manipulation of mHTT expression in defined populations, such as interneurons, MSNs, astrocytes, oligodendrocytes, microglia, vascular endothelial cells, or hypothalamic neurons, during specific developmental windows, thereby permitting causal dissection of lineage-specific and temporally distinct pathogenic mechanisms. Using these models, future research should tackle several translational objectives. Applying single-cell multi-omics, lineage tracing, and live imaging during early development will be essential for clarifying how these germline and somatic mechanisms interact across life.¹⁵⁶ Second, selectively manipulating mHTT in neurons versus glia and in progenitor versus postmitotic populations will clarify intrinsic versus non-cell-autonomous contributions.^75,157 Third, defining developmental periods in which transient suppression of mHTT yields durable rescue could provide the foundation for early intervention strategies in humans.^131,158 Fourth, these models can probe interactions between mHTT and genetic or environmental modifiers across early life, aging, and multigenerational inheritance.^123,159

Finally, experimentally testing an integrated two-component model of HD pathogenesis may require jointly manipulating early-life developmental defects and adult somatic CAG expansion. If correcting developmental vulnerabilities via early pharmacological intervention, cell type-specific mHTT suppression, or lineage-targeted rescue also amplifies the protective effects of preventing somatic expansion (e.g., through MSH3 deletion or mismatch repair modulation),^122,160 this would support a cooperative two-component model. Conversely, preventing somatic expansion in animals with uncorrected developmental abnormalities should yield only partial rescue. Such experiments will clarify how these mechanisms converge to shape HD progression and inform therapeutic timing.

Conclusion

Collectively, evidence from transgenic, KI, and LOF models suggests that HD is not solely a degenerative condition of adulthood but a disorder with deep neural developmental underpinnings.^100,139,158 Across models, mHTT disrupts fundamental processes such as progenitor cell cycle regulation,¹⁰⁸ cortical lamination, corticostriatal synapse formation,^89,153,156 and glial maturation,¹⁵⁷ often manifesting well before the emergence of classical HD symptoms.³⁹ These developmental disturbances not only precede later neuronal dysfunction but may critically shape the vulnerability and trajectory of HD pathology (Figures 1 and 2).^8,28

Figure 1.

Schematic representation of major neural developmental abnormalities implicated in Huntington's disease. Each wedge illustrates a distinct category of developmental disruption observed across various HD models, particularly during embryonic and early postnatal stages:

Circuitry Formation Abnormalities: Aberrant axonal guidance, synaptic targeting, and connectivity during brain wiring.

Figure 2.

Temporal progression of neural developmental phenotypes across mouse models of Huntington's disease. Timeline showing the emergence and progression of behavioral, cellular, molecular and circuit phenotypes in various mouse models from embryonic day 13.5 (E13.5) through postnatal week 12. Y-axis represents different mouse strains: R6/2 (Huntington's disease model), BACHD (BACHD Huntington's disease model), HdhQ250 (Huntington's disease knock-in model), HdhQ140/150 (Huntington's disease knock-in model), HdhQ111 (Huntington's disease knock-in model), and zQ175/Q175 (Huntington's disease knock-in model)^13,18,22,26^,65–67^{,86,87,90–92,108,131–137,161–173} [Created in BioRender. Yan, S. (2025) https://BioRender.com/0z75tog].

Table 1.

Summary of commonly used Huntington's disease mouse models categorized by CAG repeat length, allele type, genetic construct, and key developmental phenotypes. Transgenic models (R6/1, R6/2, BACHD) and knock-in models (HdhQ111-250, zQ175) are included to illustrate differences in disease onset, severity, and neurodevelopmental features relevant to modeling juvenile- and adult-onset Huntington's disease.

Model	CAG Size	Allele Type	Gene Characteristics	Description
R6/1	∼115	Transgenic Fragment	Human HTT exon 1 under human HTT promoter	Progressive motor and cognitive decline Disrupted cortical layering Delayed neuronal maturation Interneuron lineage misspecification
R6/2	∼150	Transgenic Fragment	Human HTT exon 1 under human HTT promoter	Early-onset seizures Neurogenesis deficits Glial dysfunction Thalamocortical projection abnormalities Interneuron mis-patterning
BACHD	∼97	Transgenic Full-Length	Full-length human HTT; floxed LoxP-STOP cassette enabling Cre-dependent expression	Early myelination defects Impaired neuronal and glial differentiation Corticostriatal synapse dysfunction Behavioral deficits emerge in infancy
HdhQ111	∼111	Knock-In	Chimeric human/mouse exon 1 inserted into endogenous mouse HTT	Subtle but early cortical mislamination Reduced neural progenitor proliferation Mitotic spindle misorientation Delayed corticostriatal synaptic development
HdhQ140	∼140		Human exon 1 inserted into endogenous mouse HTT, replacing mouse exon 1	Cortical and hippocampal LTP deficits Reduced BDNF release White matter immaturity Astrocytic dysfunction impairs neurotrophic support Post-transcriptional defects hinder OPC development and myelination
HdhQ150	∼150		Chimeric human/mouse exon 1 inserted into endogenous mouse HTT	More severe early myelination delays Glial dysfunction Synaptic dysregulation Behavioral decline
zQ175	∼190		Chimeric human/mouse exon 1 inserted into endogenous mouse HTT; floxed neomycin cassette	Early glial dysfunction Transient synaptic overconnectivity followed by excessive pruning Cortical microglial-mediated remodeling
HdhQ250	∼250		Chimeric human/mouse exon 1 inserted into endogenous mouse HTT	Severe myelination failure Impaired oligodendrocyte maturation Widespread early glial and neuronal dysfunction

Footnotes

Acknowledgements

We are grateful to trainees and faculty at Albert Einstein College of Medicine and to the many investigators whose work on developmental mechanisms in Huntington's disease has shaped the conceptual framework presented here. Figures were created with BioRender.

ORCID iDs

Yagiz M Altun

Siyu Yan

Kevin Zheng

Aldrin E Molero

Mark F Mehler

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) grant numbers: R01NS119255 (A.E.M.), R01NS125260, R21OD025320 and R03NS125224 (M.F.M.).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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