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Updated: Nov 2, 2025
Cerebellar Regional Dissection for Molecular Analysis
Published on: December 5, 2020
Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting
Sarah K Suciu1,2, Alyssa B Long2, Tamara Caspary2
1Genetics and Molecular Biology Graduate Program, Emory University, Atlanta, GA 30322, USA.
Abstract:
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.
Insights
Joubert syndrome, a ciliopathy, involves hindbrain malformations. Our study reveals ARL13B protein is crucial for cerebellar development and axon guidance, explaining aspects of the molar tooth sign.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Joubert syndrome is a ciliopathy characterized by hindbrain malformations, including the "molar tooth sign" (MTS).
- The MTS is associated with cerebellar vermis hypoplasia and aberrant superior cerebellar peduncle (SCP) white matter tract targeting.
- ARL13B, a ciliary GTPase, is implicated in Joubert syndrome pathogenesis when mutated.
Purpose of the Study:
- To investigate the role of ARL13B in cerebellar development and the etiology of the MTS using mouse models.
- To determine how ARL13B mutations affect cerebellar vermis formation and SCP axon guidance.
Main Methods:
- Utilized mouse models with genetic alterations in ARL13B.
- Analyzed cerebellar development, focusing on vermis size and SCP tract morphology via MRI and histological techniques.
- Assessed the involvement of Hedgehog signaling pathways.
Main Results:
- ARL13B is essential for proper SCP axon guidance and cerebellar vermis width.
- The Joubert syndrome-associated R79Q mutation in ARL13B did not impair Hedgehog signaling or SCP targeting in mice.
- Complete loss of ARL13B function led to a small cerebellar vermis, but the R79Q mutation did not cause vermis hypoplasia.
- A cilia-excluded, functional ARL13B variant maintained normal tract targeting and vermis width.
Conclusions:
- ARL13B plays a critical role in regulating cerebellar vermis width and SCP axon guidance, likely through Hedgehog signaling.
- The findings highlight the complex contribution of ARL13B to the molar tooth sign in Joubert syndrome, differentiating between loss-of-function and specific mutation effects.
