Poster abstracts
Poster number 48 submitted by Morgan Smith
Golgi Trafficking Protein COPB2 Regulates Neural Progenitor Survival and Reveals Species-Specific Differences in Neurogenesis
Morgan E. Smith (Molecular, Cellular, and Developmental Biology Graduate Program), Rolf W. Sottmann (Institute for Genomic Medicine at Nationwide Childrens Hospital )
Abstract:
Primary microcephaly is a neurodevelopmental disorder characterized by a significantly reduced head size at birth, often associated with a spectrum of comorbidities. To date, 30 genes involved in core cellular processes have been implicated in primary microcephaly. One of these genes, COPB2, produces the β’-COP subunit of the COPI coatomer complex. Homozygous missense variants in COPB2 identify a critical role of Golgi-ER trafficking in neuronal development. Primary microcephaly arises from aberrant neurogenesis, resulting in fewer neurons and reduced brain size. This is often caused by disruptions in processes regulating neural progenitor proliferation and differentiation. The roles of coatomer complexes and their subunits in neural progenitor behavior remain poorly understood. Our study aims to investigate the distinct involvement of COPB2 in neurogenesis and assess how pathogenic variants in the protein disrupt neuronal development. We hypothesize that COPB2 is responsible for the trafficking of key proteins involved in the maintenance of neural progenitor proliferation and differentiation, and that alterations in its binding domain compromise trafficking efficiency, thereby reducing neuronal output. The generation of a novel allelic series in mice allowed us to define the role of Copb2 in early neurogenesis through both germline and conditional knockout models. We show that the β’ subunit of the COPI coatomer complex is indispensable for embryogenesis and neural progenitor cell survival. While the factors underlying human brain complexity remain unclear, mice homozygous for a microcephaly-associated variant (R254C) are phenotypically normal, suggesting that COPB2 and proper intracellular trafficking may contribute to these processes. Our results not only strengthen our understanding of COPB2’s role in brain development, but they also highlight species-specific differences in neurogenesis and the limitations of mouse models.
References:
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Marom R et al. COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. The American Journal of Human Genetics. 2021;108(9):1710-1724. doi:10.1016/j.ajhg.2021.08.002
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Keywords: Neurogenesis, Microcephaly, Vesicle Trafficking