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This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation, and axon guidance through vertebrate Hedgehog signaling. In patients, mutations in ARL13B cause Joubert syndrome. To understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found that ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse, the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. In addition, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally showed normal tract targeting and vermis width. Taken together, our data indicate that ARL13B is critical for the control of cerebellar vermis width as well as superior cerebellar peduncle axon guidance, likely via Hedgehog signaling. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology.<\/jats:p>","DOI":"10.1093\/genetics\/iyab084","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T09:38:27Z","timestamp":1623836307000},"source":"Crossref","is-referenced-by-count":24,"title":["Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting"],"prefix":"10.1093","volume":"218","author":[{"given":"Sarah K","family":"Suciu","sequence":"first","affiliation":[{"name":"Genetics and Molecular Biology Graduate Program, Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Human Genetics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa B","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Caspary","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"2022012416325048700_iyab084-B1","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1038\/s41598-019-41940-5","article-title":"The ciliary Frizzled-like receptor Tmem67 regulates canonical Wnt\/beta-catenin signalling in the developing cerebellum via Hoxb5","volume":"9","author":"Abdelhamed","year":"2019","journal-title":"Sci Rep"},{"key":"2022012416325048700_iyab084-B2","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1093\/hmg\/dds546","article-title":"Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, 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