Journal
GENETICS
Volume 218, Issue 4, Pages -Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1093/genetics/iyab084
Keywords
molar tooth sign; Joubert syndrome; Smo; ARL13B; SCP targeting; cerebellar vermis
Categories
Funding
- National Institutes of Health [R01NS090029, R01GM110663, R35GM122549, T32GM008490, F31NS101806]
- Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities grant [P30NS055077]
- Mouse Transgenic and Gene Targeting Core (TMF) - Emory University School of Medicine
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000454]
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Patients with Joubert syndrome exhibit physical abnormalities, intellectual disability, and the characteristic molar tooth sign on MRI, caused by cerebellar vermis hypoplasia and misrouting of the superior cerebellar peduncles. Mutations in ARL13B, a cilia-enriched GTPase regulating cell fate and Hedgehog signaling, lead to Joubert syndrome. ARL13B plays a critical role in controlling cerebellar vermis width and superior cerebellar peduncle axon guidance, likely through Hedgehog signaling, highlighting its complexity in molar tooth sign etiology.
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 ciliaenriched 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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