RT Journal Article
SR Electronic
T1 Multifaceted functions of Rab23 on primary cilium and Hedgehog signaling-mediated granule cell proliferation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.01.231985
DO 10.1101/2020.08.01.231985
A1 Hor, CHH
A1 Leong, WY
A1 Goh, ELK
YR 2020
UL http://biorxiv.org/content/early/2020/08/01/2020.08.01.231985.abstract
AB Sonic Hedgehog (Shh) signaling from the primary cilium drives cerebellar granule cell precursor (GCP) proliferation. Mutations of hedgehog (Hh) pathway repressors could cause medulloblastoma, the most prevalent and malignant childhood brain tumor that arises from aberrant GCP proliferation. We demonstrate that brain-specific knockout of a Shh pathway repressor Rab23 in mice caused mis-patterning of cerebellar folia and elevated GCP proliferation during early development, but with no prevalent occurrence of medulloblastoma at adult stage. Strikingly, Rab23-depleted GCPs exhibited up-regulated basal level of Shh pathway activities despite reduced ciliation, and were desensitized against stimulations by Shh and Smoothened (Smo) agonist in primary GCP culture. These results illustrate dual functions of Rab23 in repressing the basal level of Shh signaling, while facilitating Shh signal transduction via Shh/Smo on primary cilium. Collectively, our findings unravel instrumental roles of Rab23 in GCP proliferation and ciliogenesis. Rab23’s potentiation of Shh signaling pathway through the primary cilium and Smo, suggests a potential new therapeutic for Smo/primary cilium-driven medulloblastoma.Author Summary C.H.H conceived, designed, lead, and performed all in vitro and in vivo experiments, analyzed data and wrote the manuscript. W.Y performed QPCR experiments and primary GCP cultures and analyzed data. E.L.G conceived and directed the study.Competing Interest StatementThe authors have declared no competing interest.