Transventricular delivery of Sonic hedgehog is essential to cerebellar ventricular zone development

Huang, Xi; Liu, Jiang; Ketova, Tatiana; Fleming, Jonathan T.; Grover, Vandana K.; Cooper, Michael K.; Litingtung, Ying; Chiang, Chin

doi:10.1073/pnas.0911838107

Cited by 149 publications

(171 citation statements)

References 36 publications

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“…Although we were not able to detect the expression of SHH in PCs before 17 gw, we observed that GCPs expressed GLI1 at all stages analyzed (Fig. 3B), suggesting that an additional source of SHH might exist before 17 gw (32,33). However, SHH mRNA expression detected in the PCs from 17 gw coincides with a peak in GCP proliferation (Figs.…”

Section: Gcp Proliferation Is Similar In Cerebellar Vermis and Hemispmentioning

confidence: 44%

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Aguilar

Meunier

Strehl

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results, obtained from the analysis of human samples, show that the hemispheres and the vermis are affected in JS/MKS and provide evidence of a defective cellular mechanism in these pathologic processes.cilia | granular neuron | hindbrain | developmental pathology J oubert syndrome (JS; Online Mendelian Inheritance in Man no. 213300) and Meckel syndrome (MKS; Online Mendelian Inheritance in Man no. 249000) are believed to represent the two extremes of the same multisystemic disorder. JS is characterized by a complex malformation of the cerebellum/brainstem, the most striking feature of which is hypoplasia or complete aplasia of the cerebellar vermis (1, 2). In MKS, which is lethal in utero, this defect is associated with occipital encephalocele or anencephaly, severely cystic kidneys, and abnormal liver and skeleton. To date, 16 genes responsible for JS (NPHP1, AHI1, ARL13B, INPP5E, KIF7, OFD1, TCTN1, and CEP41), MKS (MKS1, B9D1, and B9D2), or both (RPGRIP1L, CEP290, CC2D2A, TMEM216, TMEM67/MKS3, and TCTN2) have been identified (3-6). Although all JS/MKS genes encode a ciliary/basal body (BB) protein, which is compelling evidence that the primary cilium is involved in these pathologic conditions, the cellular mechanisms by which cilium dysfunction leads to severe brain malformations remain a mystery.Because the use of human subjects to study human pathologies is problematic, insight into diseases usually comes from the analysis of murine models. However, none of the currently available murine models of JS/MKS faithfully recapitulate the cerebellar phenotype seen in JS/MKS. Interestingly, in ciliary conditional mutant mice, the cerebellum is hypoplastic and Sonic hedgehog (Shh)-dependent proliferation of granule cell progenitors (GCPs) is sev...

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Section: Gcp Proliferation Is Similar In Cerebellar Vermis and Hemispmentioning

confidence: 44%

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Aguilar

Meunier

Strehl

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Decreasing hydrostatic pressure results in smaller brain ventricles, and smaller and disorganized neural tissue [63]. Factors within the embryonic CSF, including sonic hedgehog and choroid plexus-derived insulin-like growth factor 2, promote the proliferation of neural progenitors [59,78,90,170]. The CSF effect is optimal when age-matched CSF and tissue are combined, highlighting the dynamic nature of both the choroid plexus/CSF axis and of the intrinsic state of the responding cells [18,78].…”

Section: Embryonic and Postnatal Developmentmentioning

confidence: 99%

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

et al. 2018

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The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the developing and adult brain, and CSF compartments are key to the immune surveillance of the CNS. In these contexts, the choroid plexuses are an important source of biologically active molecules involved in brain development, stem cell proliferation and differentiation, and brain repair. By sensing both physiological changes in brain homeostasis and peripheral or central insults such as inflammation, they also act as sentinels for the CNS. Finally, their role in the control of immune cell traffic between the blood and the CSF confers on the choroid plexuses a function in neuroimmune regulation and implicates them in neuroinflammation. The choroid plexuses, therefore, deserve more attention while investigating the pathophysiology of CNS diseases and related comorbidities.

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“…essential to regulate the proliferation of radial glia and, consequently, the expansion of GABAergic interneurons [98]. In this case, however, endogenous PCs are not the source of Shh ligand, which is secreted by the choroid plexi and transventricularly delivered by the embryonic cerebrospinal fluid [98].…”

Section: Shh and Gabaergic Interneuronsmentioning

confidence: 99%

“…This morphogen, secreted by Purkinje cells from E17.5 [95][96][97] and by choroid plexi at earlier time points [98], controls the production of appropriate numbers of excitatory and inhibitory interneurons (Fig. 2).…”

Section: Cerebellar Territory and Germinal Zonesmentioning

confidence: 99%

Sonic hedgehog patterning during cerebellar development

Luca

Cerrato

Fucà

et al. 2015

Cell. Mol. Life Sci.

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Abstract:Robust evidence in literature indicates that the morphogenic factor Sonic Hedgehog (Shh) actively orchestrates several aspects of cerebellar development and maturation. During embryogenesis Shh signalling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Purkinje cell (PC)-secreted Shh sustains the amplification of neurogenic niches active during postnatal development: the external granular layer (EGL) and the prospective white matter (PWM) where excitatory granule cells and inhibitory interneurons, respectively, are produced. In addition, Shh signalling acts on Bergmann glia differentiation and during development sustains cerebellar foliation. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying the role of this ligand in the development of different cerebellar phenotypes. Keywords: Shh, mitogen, differentiation, cerebellum.Authors declare no conflict of interest. AbstractRobust evidence in literature indicates that the morphogenic factor Sonic Hedgehog (Shh) actively orchestrates several aspects of cerebellar development and maturation. During embryogenesis Shh

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Transventricular delivery of Sonic hedgehog is essential to cerebellar ventricular zone development

Cited by 149 publications

References 36 publications

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

Sonic hedgehog patterning during cerebellar development

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