Recognition that virtually every neuronal progenitor cell and neuron in the cerebral cortex is ciliated has triggered intense interest in neuronal cilia function. Here, we review recent studies that suggest the primary cilia of cortical progenitor cells are required for establishing and maintaining the organization within pools of proliferative cells. In addition, signaling via primary cilia differentially influence the migration and differentiation of excitatory and inhibitory neurons in the developing cortex. Specifically, the primary cilia of excitatory neurons appear to play a significant role in regulating the post-migratory differentiation of these neurons whereas cilia of inhibitory neurons appear to be required for the proper migration and positioning of those cells in cortex. Given the recently discovered functions of cilia in proliferation, neuronal migration, and differentiation, it is likely that further studies of cilia signaling will improve our understanding of how these basic developmental processes are regulated and may provide insight into how mutations in specific cilia genes linked to ciliopathies lead to the many neurological deficits associated with these diseases.
Amador-ArjonaAElliottJMillerAGinbeyAPazourGJEnikolopovG, and others. 2011. Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory. J Neurosci31:9933–44.
2.
AnastasSBMuellerDSemple-RowlandSLBreunigJJSarkisianMR. 2011. Failed cytokinesis of neural progenitors in citron kinase-deficient rats leads to multiciliated neurons. Cereb Cortex21:338–44.
3.
ArellanoJIGuadianaSMBreunigJJRakicPSarkisianMR. 2012. Development and distribution of neuronal cilia in mouse neocortex. J Comp Neurol520:848–73.
4.
BaudoinJPViouLLaunayPSLuccardiniCEspeso GilSKiyasovaV, and others. 2012. Tangentially migrating neurons assemble a primary cilium that promotes their reorientation to the cortical plate. Neuron76:1108–22.
BerbariNFJohnsonADLewisJSAskwithCCMykytynK. 2008a. Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors. Mol Biol Cell19:1540–7.
7.
BerbariNFLewisJSBishopGAAskwithCCMykytynK. 2008b. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A105:4242–6.
8.
BesseLNetiMAnselmeIGerhardtCRutherULaclefC, and others. 2011. Primary cilia control telencephalic patterning and morphogenesis via Gli3 proteolytic processing. Development138:2079–88.
9.
BishopGABerbariNFLewisJMykytynK. 2007. Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol505:562–71.
10.
BrailovIBancilaMBrisorgueilMJMiquelMCHamonMVergeD. 2000. Localization of 5-HT(6) receptors at the plasma membrane of neuronal cilia in the rat brain. Brain Res872:271–5.
11.
BreunigJJSarkisianMRArellanoJIMorozovYMAyoubAESojitraS, and others. 2008. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc Natl Acad Sci U S A105:13127–32.
12.
CasparyTLarkinsCEAndersonKV. 2007. The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell12:767–78.
13.
ChakravarthyBGaudetCMenardMAtkinsonTChiariniADal PraI, and others. 2010. The p75 neurotrophin receptor is localized to primary cilia in adult murine hippocampal dentate gyrus granule cells. Biochem Biophys Res Commun401:458–62.
14.
ChihBLiuPChinnYChalouniCKomuvesLGHassPE, and others. 2011. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol14:61–72.
15.
CorbitKCAanstadPSinglaVNormanARStainierDYReiterJF. 2005. Vertebrate Smoothened functions at the primary cilium. Nature437:1018–21.
16.
CorbitKCShyerAEDowdleWEGauldenJSinglaVChenMH, and others. 2008. Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol10:70–6.
17.
DahlHA. 1963. Fine structure of cilia in rat cerebral cortex. Z Zellforsch Mikrosk Anat60:369–86.
18.
DasRMStoreyKG. 2014. Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science343:200–4.
19.
DavenportJRWattsAJRoperVCCroyleMJvan GroenTWyssJM, and others. 2007. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol17:1586–94.
20.
DeCaenPGDellingMVienTNClaphamDE. 2014. Direct recording and molecular identification of the calcium channel of primary cilia. Nature504:315–8.
21.
DellingMDeCaenPGDoernerJFFebvaySClaphamDE. 2014. Primary cilia are specialized calcium signalling organelles. Nature504:311–4.
22.
DomireJSGreenJALeeKGJohnsonADAskwithCCMykytynK. 2011. Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins. Cell Mol Life Sci68:2951–60.
23.
DomireJSMykytynK. 2009. Markers for neuronal cilia. Methods Cell Biol91:111–21.
24.
DubreuilVMarzescoAMCorbeilDHuttnerWBWilsch-BrauningerM. 2007. Midbody and primary cilium of neural progenitors release extracellular membrane particles enriched in the stem cell marker prominin-1. J Cell Biol176:483–95.
25.
EggenschwilerJTAndersonKV. 2007. Cilia and developmental signaling. Annu Rev Cell Dev Biol23:345–73.
26.
EinsteinEBPattersonCAHonBJReganKAReddiJMelnikoffDE, and others. 2010. Somatostatin signaling in neuronal cilia is critical for object recognition memory. J Neurosci30:4306–14.
27.
EnglundCFinkALauCPhamDDazaRABulfoneA, and others. 2005. Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci25:247–51.
28.
FuchsJLSchwarkHD. 2004. Neuronal primary cilia: a review. Cell Biol Int28:111–8.
29.
Garcia-GonzaloFRReiterJF. 2012. Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access. J Cell Biol197:697–709.
30.
GoetzSCOcbinaPJAndersonKV. 2009. The primary cilium as a Hedgehog signal transduction machine. Methods Cell Biol94:199–222.
31.
GreenJAGuCMykytynK. 2012. Heteromerization of ciliary G protein-coupled receptors in the mouse brain. PLoS One7:e46304.
32.
GreenJAMykytynK. 2010. Neuronal ciliary signaling in homeostasis and disease. Cell Mol Life Sci67:3287–97.
33.
GreenJAMykytynK. 2014. Neuronal primary cilia: an underappreciated signaling and sensory organelle in the brain. Neuropsychopharmacology39:244–5.
34.
GuadianaSMSemple-RowlandSLDaroszewskiDMadorskyIBreunigJJMykytynK, and others. 2013. Arborization of dendrites by developing neocortical neurons is dependent on primary cilia and type 3 adenylyl cyclase. J Neurosci33:2626–38.
35.
HamonMDoucetELefèvreKMiquelMCLanfumeyLInsaustiR, and others. 1999. Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors. Neuropsychopharmacology21(2 Suppl):68S–76S.
36.
HanYGSpasskyNRomaguera-RosMGarcia-VerdugoJMAguilarASchneider-MaunouryS, and others. 2008. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci11:277–84.
37.
HandelMSchulzSStanariusASchreffMErdtmann-VourliotisMSchmidtH, and others. 1999. Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience89:909–26.
38.
HaycraftCJBanizsBAydin-SonYZhangQMichaudEJYoderBK. 2005. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet1:e53.
39.
HigginbothamHEomTYMarianiLEBachledaAHirtJGukassyanV, and others. 2012. Arl13b in primary cilia regulates the migration and placement of interneurons in the developing cerebral cortex. Dev Cell23:925–38.
40.
HigginbothamHGuoJYokotaYUmbergerNLSuCYLiJ, and others. 2013. Arl13b-regulated cilia activities are essential for polarized radial glial scaffold formation. Nat Neurosci16:1000–7.
41.
HsiaoYCTuzKFerlandRJ. 2012. Trafficking in and to the primary cilium. Cilia1:4.
42.
HuangfuDAndersonKV. 2005. Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A102:11325–30.
43.
HuangfuDLiuARakemanASMurciaNSNiswanderLAndersonKV. 2003. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature426:83–7.
44.
KimAHPuramSVBilimoriaPMIkeuchiYKeoughSWongM, and others. 2009. A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons. Cell136:322–36.
45.
KozminskiKGBeechPLRosenbaumJL. 1995. The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J Cell Biol131:1517–27.
46.
KozminskiKGJohnsonKAForscherPRosenbaumJL. 1993. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci U S A90:5519–23.
47.
KumamotoNGuYWangJJanoschkaSTakemaruKLevineJ, and others. 2012. A role for primary cilia in glutamatergic synaptic integration of adult-born neurons. Nat Neurosci15:399–405.
LancasterMAGleesonJG. 2009. The primary cilium as a cellular signaling center: lessons from disease. Curr Opin Genet Dev19:220–9.
50.
LeaskAObrietanKStearnsT. 1997. Synaptically coupled central nervous system neurons lack centrosomal gamma-tubulin. Neurosci Lett229:17–20.
51.
LiASaitoMChuangJZTsengYYDedesmaCTomizawaK, and others. 2011. Ciliary transition zone activation of phosphorylated Tctex-1 controls ciliary resorption, S-phase entry and fate of neural progenitors. Nat Cell Biol13:402–11.
52.
LiangHHippenmeyerSGhashghaeiHT. 2012. A Nestin-cre transgenic mouse is insufficient for recombination in early embryonic neural progenitors. Biol Open1:1200–3.
53.
LiuAWangBNiswanderLA. 2005. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development132:3103–11.
54.
LoktevAVJacksonPK. 2013. Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell Rep5:1316–29.
55.
LoTurcoJJBaiJ. 2006. The multipolar stage and disruptions in neuronal migration. Trends Neurosci29:407–13.
56.
LouviAGroveEA. 2011. Cilia in the CNS: the quiet organelle claims center stage. Neuron69:1046–60.
57.
MandlLMegeleR. 1989. Primary cilia in normal human neocortical neurons. Z Mikrosk Anat Forsch103:425–30.
58.
MarszalekJRRuiz-LozanoPRobertsEChienKRGoldsteinLS. 1999. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc Natl Acad Sci U S A96:5043–8.
59.
MassinenSHokkanenMEMatssonHTammimiesKTapia-PaezIDahlstrom-HeuserV, and others. 2011. Increased expression of the dyslexia candidate gene DCDC2 affects length and signaling of primary cilia in neurons. PLoS ONE6:e20580.
60.
MaySRAshiqueAMKarlenMWangBShenYZarbalisK, and others. 2005. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol287:378–89.
61.
MiyoshiKOnishiKAsanumaMMiyazakiIDiaz-CorralesFJOgawaN. 2006. Embryonic expression of pericentrin suggests universal roles in ciliogenesis. Dev Genes Evol216:537–42.
62.
PampliegaOOrhonIPatelBSridharSDiaz-CarreteroABeauI, and others. 2014. Functional interaction between autophagy and ciliogenesis. Nature502:194–200.
63.
ParidaenJTWilsch-BrauningerMHuttnerWB. 2013. Asymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division. Cell155:333–44.
64.
PetersAPalaySLWebsterHF. 1976. The fine structure of the nervous system: the neurons and supporting cells. Philadelphia: W. B. Saunders.
65.
PuramSVKimAHIkeuchiYWilson-GradyJTMerdesAGygiSP, and others. 2011. A CaMKIIβ signaling pathway at the centrosome regulates dendrite patterning in the brain. Nat Neurosci14:973–83.
66.
RaoSGeSShellyM. 2012. Centrosome positioning and primary cilia assembly orchestrate neuronal development. Front Biol7:412–27.
67.
RohatgiRMilenkovicLScottMP. 2007. Patched1 regulates hedgehog signaling at the primary cilium. Science317:372–6.
68.
SandersTALlagosteraEBarnaM. 2013. Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature497:628–32.
69.
SchmechelDERakicP. 1979. A Golgi study of radial glial cells in developing monkey telencephalon: morphogenesis and transformation into astrocytes. Anat Embryol (Berl)156:115–52.
70.
SoetedjoLGloverDAJinH. 2013. Targeting of vasoactive intestinal peptide receptor 2, VPAC2, a secretin family G-protein coupled receptor, to primary cilia. Biol Open2:686–94.
71.
SorokinS. 1962. Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J Cell Biol15:363–77.
72.
StanicDMalmgrenHHeHScottLAperiaAHokfeltT. 2009. Developmental changes in frequency of the ciliary somatostatin receptor 3 protein. Brain Res1249:101–12.
73.
StottmannRWTranPVTurbe-DoanABeierDR. 2009. Ttc21b is required to restrict sonic hedgehog activity in the developing mouse forebrain. Dev Biol335:166–78.
74.
SunXHaleyJBulgakovOVCaiXMcGinnisJLiT. 2012. Tubby is required for trafficking G protein-coupled receptors to neuronal cilia. Cilia1:21.
75.
TangZLinMGStoweTRChenSZhuMStearnsT, and others. 2014. Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature502:254–7.
76.
TanosBEYangHJSoniRWangWJMacalusoFPAsaraJM, and others. 2013. Centriole distal appendages promote membrane docking, leading to cilia initiation. Genes Dev27:163–8.
77.
TownTBreunigJJSarkisianMRSpilianakisCAyoubAELiuX, and others. 2008. The stumpy gene is required for mammalian ciliogenesis. Proc Natl Acad Sci U S A105:2853–8.
78.
TramontinADGarcia-VerdugoJMLimDAAlvarez-BuyllaA. 2003. Postnatal development of radial glia and the ventricular zone (VZ): a continuum of the neural stem cell compartment. Cereb Cortex13:580–7.
79.
TuckerKLCasparyT, editors. 2013. Cilia and nervous system development and function. Dordrecht: Springer.
80.
ValenteEMRostiROGibbsEGleesonJG. 2014. Primary cilia in neurodevelopmental disorders. Nat Rev Neurol10:27–36.
81.
VierkottenJDildropRPetersTWangBRütherU. 2007. Ftm is a novel basal body protein of cilia involved in Shh signalling. Development134:2569–77.
82.
WangZPhanTStormDR. 2011. The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. J Neurosci31:5557–61.
WillaredtMAHasenpusch-TheilKGardnerHAKitanovicIHirschfeld-WarnekenVCGojakCP, and others. 2008. A crucial role for primary cilia in cortical morphogenesis. J Neurosci28:12887–900.
85.
Wilsch-BrauningerMPetersJParidaenJTHuttnerWB. 2012. Basolateral rather than apical primary cilia on neuroepithelial cells committed to delamination. Development139:95–105.
86.
WilsonSLWilsonJPWangCWangBMcConnellSK. 2012. Primary cilia and Gli3 activity regulate cerebral cortical size. Dev Neurobiol72:1196–212.
87.
WoodCRHuangKDienerDRRosenbaumJL. 2013. The cilium secretes bioactive ectosomes. Curr Biol23:906–11.
88.
WuKSTangTK. 2012. CPAP is required for cilia formation in neuronal cells. Biol Open1:559–65.
89.
YangJGaoJAdamianMWenXHPawlykBZhangL, and others. 2005. The ciliary rootlet maintains long-term stability of sensory cilia. Mol Cell Biol25:4129–37.
90.
YoshimuraKTakedaS. 2012. Hedgehog signaling regulates myelination in the peripheral nervous system through primary cilia. Differentiation83:S78–85.
