Inhibition of Sar1b, the Gene Implicated in Chylomicron Retention Disease, Impairs Migration and Morphogenesis of Developing Cortical Neurons
| Autor: | Meifang Yan, Xiaomeng Tu, Hao Zhu, Ruru Feng, Zhiqiang Guo, Jie-Guang Chen, Li Yan, Xue Li, Sidney Yu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Biology Hypobetalipoproteinemias White matter Mice 03 medical and health sciences symbols.namesake 0302 clinical medicine Malabsorption Syndromes Cell Movement Morphogenesis medicine Animals Humans Secretory pathway Monomeric GTP-Binding Proteins Cerebral Cortex Neurons Neocortex General Neuroscience Endoplasmic reticulum SAR1B Golgi apparatus medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure nervous system Cerebral cortex biology.protein symbols 030217 neurology & neurosurgery Chylomicron retention disease |
| Zdroj: | Neuroscience. 449:228-240 |
| ISSN: | 0306-4522 |
| DOI: | 10.1016/j.neuroscience.2020.09.044 |
| Popis: | Chylomicron Retention Disease (CMRD) is a rare inherited lipid malabsorption syndrome that exhibits a recessive hypocholesterolemia in infants. CMRD has been associated with genetic mutations of SAR1B-a member of the Arf GTPase family involved in the secretory pathway from the endoplasmic reticulum to the Golgi. CMRD patients suffer from multiple neurological deficits, the etiologies of which remain unclear. In this study, we found that Sar1b protein is expressed in developing mouse neocortex. The knockdown of Sar1b does not affect the proliferation and mitotic exit of the neural progenitors but inhibits the radial migration of the newborn cortical neurons. At postnatal day 3, the neurons stalled in the white matter fail to develop axons across the midline of the corpus callosum, resulting in the loss of the neurons later on. hSAR1B(D137N), a CMRD-associated mutant of SAR1B, also impairs the positioning of the cortical neurons in the mouse brain, suggesting a dominant-negative effect by the human heterozygous mutant. The results indicate that SAR1B is crucial to radial migration and axon morphogenesis of the cortical neurons. Our study reveals a cell-autonomous action of Sar1b, which is unrelated to lipid absorption from the gut, on the development of the cerebral cortex. |
| Databáze: | OpenAIRE |
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