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Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting.
Suciu, Sarah K; Long, Alyssa B; Caspary, Tamara.
Affiliation
  • Suciu SK; Genetics and Molecular Biology Graduate Program, Emory University, Atlanta, GA 30322, USA.
  • Long AB; Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
  • Caspary T; Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Genetics ; 218(4)2021 08 09.
Article in En | MEDLINE | ID: mdl-34132778
Patients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and a hindbrain malformation described as the "molar tooth sign" due to its appearance on an MRI. 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Retina / Abnormalities, Multiple / Cerebellum / Eye Abnormalities / ADP-Ribosylation Factors / Kidney Diseases, Cystic / Cerebral Peduncle / Smoothened Receptor Type of study: Prognostic_studies Limits: Animals Language: En Journal: Genetics Year: 2021 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Retina / Abnormalities, Multiple / Cerebellum / Eye Abnormalities / ADP-Ribosylation Factors / Kidney Diseases, Cystic / Cerebral Peduncle / Smoothened Receptor Type of study: Prognostic_studies Limits: Animals Language: En Journal: Genetics Year: 2021 Document type: Article Affiliation country: United States Country of publication: United States