Thursday, March 13, 2025
3/13/2025
Project Summary Primary microcephaly is a structural birth defect characterized by a significantly smaller head circumference than the mean of age and gender at birth. It is mainly linked to dysfunction of the neural progenitor cell population, resulting in reduced neurons in the cerebral cortex. Most microcephaly-causing genes are involved in mitosis and cytokinesis; however, recently, defects in secretory protein trafficking have been implicated in causing microcephaly. One of the newly identified genes that are potentially involved in protein trafficking is IER3IP1. Bi-allelic variants of IER3IP1 have been reported to cause a rare, pediatric, neurodevelopmental condition called microcephaly with simplified gyration, generalized epilepsy, and permanent neonatal diabetes syndrome (MEDS). MEDS patients present with severe congenital structural brain abnormalities, including microcephaly, ventriculomegaly, and cerebral atrophy. Prior studies on IER3IP1 suggest that its function is involved in ER to the Golgi trafficking in humans. I confirmed that the pathogenic variant blocks ER to Golgi trafficking with a GFP trafficking reporter, and the correction of IER3IP1 mutation through CRISPR/Cas9 restored the trafficking efficiency. Herein, I propose to focus on elucidating the function of IER3IP1 in neurogenesis and human brain development to understand how faulty protein trafficking leads to brain birth defects. I hypothesize that IER3IP1 regulates secretory protein trafficking during neurogenesis. I have successfully generated and characterized cortical brain organoids and 2D neuronal culture derived from MEDS patient-derived induced pluripotent stem cells and isogenic control cells to test this. Using these MEDS patient cell models, I will complete the following aims: Aim 1. What is the underlying cellular mechanism of microcephaly seen in MEDS patients with IER3IP1 p.L78P mutation? and Aim 2. Does IER3IP1 regulate the molecular trafficking of membrane receptors important in neurodevelopment? This proposal will fill the gap in our understanding of how protein trafficking regulates neurogenesis and provide insight into how abnormal protein trafficking leads to structural brain abnormalities.
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