当前位置: X-MOL 学术Genetics › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting.
GENETICS ( IF 3.3 ) Pub Date : 2021-06-16 , DOI: 10.1093/genetics/iyab084
Sarah K Suciu 1, 2 , Alyssa B Long 2 , Tamara Caspary 2
Affiliation  

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. In order to understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found 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. Additionally, 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 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.

中文翻译:

Smoothened 和 ARL13B 在小鼠中对于高级小脑脚的定位至关重要。

患有纤毛病 Joubert 综合征的患者表现出身体异常、智力障碍和后脑畸形,由于其在 MRI 上的出现被称为“臼齿征”。这种放射学异常是由小脑蚓部发育不全和小脑上脚白质束不当靶向共同引起的。ARL13B 是一种富含纤毛的调节性 GTP 酶,可通过脊椎动物 Hedgehog 信号传导调节细胞命运、细胞增殖和轴突导向。在患者中,ARL13B 的突变会导致 Joubert 综合征。为了了解磨牙征的病因,我们使用小鼠模型来研究 ARL13B 在小脑发育过程中的作用。我们发现 ARL13B 调节小脑上脚的定位,这些纤维束需要 Hedgehog 信号进行正确引导。然而,在小鼠中,ARL13B 中引起 Joubert 的 R79Q 突变不会破坏 Hedgehog 信号,也不会影响道靶向。我们在缺乏 ARL13B 功能的小鼠中发现了一个小的小脑蚓部,但在表达引起 Joubert 的 R79Q 突变的小鼠中没有发现小脑蚓部发育不全。此外,表达正常转导 Hedgehog 的 ARL13B 纤毛排除变体的小鼠显示出正常的束靶向和蚯蚓宽度。总之,我们的数据表明 ARL13B 对于控制小脑蚓部宽度以及小脑上脚轴突引导至关重要,可能通过 Hedgehog 信号传导。因此,我们的工作突出了 ARL13B 在磨牙牙征病因学中的复杂性。
更新日期:2021-07-06
down
wechat
bug