A Crucial Role for Primary Cilia in Cortical Morphogenesis

Willaredt, Marc A.; Hasenpusch‐Theil, Kerstin; Gardner, Humphrey; Kitanovic, Igor; Hirschfeld-Warneken, Vera C.; Gojak, Christian; Gorgas, Karin; Bradford, Chad; Spatz, Joachim P.; Wölfl, Stefan; Theil, Thomas; Tucker, Kerry L.

doi:10.1523/jneurosci.2084-08.2008

Cited by 128 publications

(171 citation statements)

References 78 publications

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“…S1B-E). In FoxG1-K3A cKO mice, cilia depletion in NEP cells leads to patterning defects and altered GLI3 processing, as previously reported (Benadiba et al, 2012;Besse et al, 2011;Higginbotham et al, 2013;Willaredt et al, 2008;Laclef et al, 2015;Fig. S1F-H).…”

Section: Ventricular Morphogenesis Defects In Ciliary Mutantssupporting

confidence: 78%

“…Here, we used conditional knockout of ciliary genes (Ift88 and Kif3a) in Nestin-Cre mice to deplete RGCs of their primary cilium, bypassing its role in brain patterning and the polarity of neuroepithelial cells (Benadiba et al, 2012;Besse et al, 2011;Higginbotham et al, 2013;Willaredt et al, 2008;Wilson et al, 2011). Although Nestin-Cre expression starts around E10.5 in the forebrain, cilia abrogation in the VZ was complete only at E14.5, as previously shown (Liang et al, 2012; Fig.…”

Section: Discussionmentioning

confidence: 72%

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mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis

Foerster¹,

Daclin²,

Shihavuddin³

et al. 2017

Journal of Cell Science

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Radial glial cells (RCGs) are self-renewing progenitor cells that give rise to neurons and glia during embryonic development. Throughout neurogenesis, these cells contact the cerebral ventricles and bear a primary cilium. Although the role of the primary cilium in embryonic patterning has been studied, its role in brain ventricular morphogenesis is poorly characterized. Using conditional mutants, we show that the primary cilia of radial glia determine the size of the surface of their ventricular apical domain through regulation of the mTORC1 pathway. In cilium-less mutants, the orientation of the mitotic spindle in radial glia is also significantly perturbed and associated with an increased number of basal progenitors. The enlarged apical domain of RGCs leads to dilatation of the brain ventricles during late embryonic stages (ventriculomegaly), which initiates hydrocephalus during postnatal stages. These phenotypes can all be significantly rescued by treatment with the mTORC1 inhibitor rapamycin. These results suggest that primary cilia regulate ventricle morphogenesis by acting as a brake on the mTORC1 pathway. This opens new avenues for the diagnosis and treatment of hydrocephalus.

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Section: Ventricular Morphogenesis Defects In Ciliary Mutantssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 72%

mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis

Foerster¹,

Daclin²,

Shihavuddin³

et al. 2017

Journal of Cell Science

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“…Importantly, a ciliary localization motif in Smo appears to control Smo translocation to the cilium (Corbit et al, 2005). Subsequent findings have demonstrated that Gli proteins and Sufu (a negative regulator of Gli) also localize to the primary cilium where, like other IFT proteins, they regulate physiological processes such as limb development and cell migration to the brain and craniofacial skeleton (Corbit et al, 2005;Han et al, 2008;Rohatgi et al, 2007;Spassky et al, 2008;Tobin et al, 2008;Willaredt et al, 2008). …”

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confidence: 99%

Cilia in vertebrate development and disease

2012

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SummaryThrough the combined study of model organisms, cell biology, cell signaling and medical genetics we have significantly increased our understanding of the structure and functions of the vertebrate cilium. This ancient organelle has now emerged as a crucial component of certain signaling and sensory perception pathways in both developmental and homeostatic contexts. Here, we provide a snapshot of the structure, function and distribution of the vertebrate cilium and of the pathologies that are associated with its dysfunction. Key words: Cilia, IFT, Signaling IntroductionOnce considered to be vestigial organelles, cilia are microtubulebased structures found in unicellular flagellates and in multicellular organisms and have recently been discovered to have a profound influence on tissue development and homeostasis. Although the presence of cilia is restricted to specific cell types in invertebrates, their near ubiquitous localization on the apical surface of most vertebrate cell types suggests that this ancient organelle has evolved to facilitate a broad range of functions. Recent findings in humans and in model organisms have fuelled a renewed interest in the cilium as a sensory hub and as generator of fluid flow; both of these functions underpin fascinating developmental processes, such as the initiation of left-right (L-R) asymmetry (Hirokawa et al., 2006), as well as certain disease pathologies, such as the modulation of cancer progression and metastasis (Han et al., 2009;Wong et al., 2009). Consistent with the developmental roles of the cilium in vertebrates in fluid flow generation, mechanosensation, osmosensation, olfaction, photoreception, chemosensation and thermosensation (Berbari et al., 2009; Hirokawa et al., 2006), and based on the diverse range of cell types that can form a cilium, the clinical features of several human disorders have been attributed to dysfunctional cilia. In this poster article, we provide an overview of ciliary biology with an emphasis on signaling pathways and modes of ciliary dysfunction in which selected ciliary expression is associated with specific developmental events and disease states. Development 139, 443-448 (2012) (Gerdes et al., 2009;Olsen, 2005), cilia are microtubule-based structures that can be classified as immotile 9+0 primary cilia or motile 9+2 cilia, depending on the presence of a central microtubule pair that is surrounded by nine pairs of microtubule doublets (Satir and Christensen, 2007). However, exceptions to these traditional classifications do occur; renal cilia have a motile 9+0 configuration (Kramer-Zucker et al., 2005), motile cilia of the mouse embryonic node have both 9+0 and 9+2 configurations (Caspary et al., 2007;Nonaka et al., 1998), and cilia in the frog appear to have an immotile 9+2 design (Reese, 1965). Although the number of motile cilia can range from 200 to 300 per cell type, a single immotile primary cilium is typically present on most cell types.Pioneering studies in the green alga Chlamydomonas reinhardtii delineated a dynamic...

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“…[14][15][16] Likewise, targeted deletion of Arl13b at different developmental stages in mice forebrain, although apparently not affecting the early neuroepithelium, caused the reversion of apico-basal polarity of the radial glia scaffold, with the concomitant misplacement of radially-migrating neurons. 17 Importantly, the integrity of neuroepithelial polarity has been tightly correlated with asymmetry in neurogenic cell divisions, and primary cilia may also have a role in the regulation of this process.…”

Section: Cilia and The Cell Proliferation/neurogenesis Balancementioning

confidence: 99%

Neuron's little helper: The role of primary cilia in neurogenesis

2016

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The generation of new neurons involves a great variety of cell-extrinsic and cell-intrinsic signals. The primary cilium, long regarded as an "evolutionary vestige," has emerged as an essential signaling hub in many cells, including neural progenitors and differentiating neurons. Most progenitors harbor an apically-localized primary cilium, which is assembled and disassembled following the cell cycle, while the presence, position and length of this organelle appears to be even more variable in differentiating neurons. One of the main extracellular cues acting through the cilium is Sonic Hedgehog, which modulates spatial patterning, the progression of the cell cycle and the timing of neurogenesis. Other extracellular signals appear to bind to cilia-localized receptors and affect processes such as dendritogenesis. All the observed dynamics, as well as the many signaling pathways depending on cilia, indicate this organelle as an important structure involved in neurogenesis.

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A Crucial Role for Primary Cilia in Cortical Morphogenesis

Cited by 128 publications

References 78 publications

mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis

mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis

Cilia in vertebrate development and disease

Neuron's little helper: The role of primary cilia in neurogenesis

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