Distinguishing the role of ERC1 isoforms in membrane trafficking during craniofacial and neuronal development

点击翻译按钮获取中文摘要

Project Summary/Abstract Membrane trafficking is an essential cellular mechanism contributing to cell shape changes and tissue integrity during development. Mutations impairing proper trafficking can result in developmental disorders, affecting both craniofacial morphology and neurologic function. Clinical reports have identified both craniofacial phenotypes and neurodevelopmental disorders associated with distal chromosome 12 deletions. ERC1 (ELKS, Rab6IP2, CAST), a regulator of membrane trafficking, is found within the smallest region of overlap between deleted chromosome 12 regions. However, a role for ERC1 in regulating craniofacial and neuronal development has not been easy to determine, particularly due to multiple alternatively spliced ERC1 isoforms. Human ERC1 isoforms are reported to be differentially expressed, and therefore, could have distinct cellular function. Unlike other vertebrate models, zebrafish have two paralogous erc1 genes, erc1a and erc1b, both of which are homologous to alternatively spliced human ERC1 isoforms. By forward genetics screen or CRISPR/Cas9 genome editing in zebrafish, we propose to examine the role of erc1 paralogs in craniofacial cartilage and brain morphology during development. The aims of this project are to a) identify zebrafish erc1 paralogs’ function in craniofacial cartilage and neural tissue morphology during development, and b) determine Erc1 paralogs’ function in establishing cell shape and cell survival through Rab GTPase interaction during development. This project uses in vivo vertebrate animal modeling and imaging techniques to map distinct functional contribution of human ERC1 isoforms to craniofacial and neuronal development. Investigating the molecular function of separate ERC1 isoforms in cell shape and survival during development will provide insight into a cellular basis to craniofacial dysmorphology and neurodevelopmental disorder comorbidity occurring in patients with distal chromosome 12 deletions.