ORCID

http://orcid.org/0000-0002-4148-7420

Date of Award

Winter 12-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Recent human genetic studies have associated mutations in a gene called Myelin Transcription Factor 1 Like (MYT1L) with neurodevelopmental disorders (NDDs). Patients with MYT1L loss of function (LoF) mutations (MYT1L Syndrome patients) demonstrate shared symptoms such as microcephaly, attention deficit and hyperactivity disorder (ADHD), and obesity. Despite prior studies showing MYT1L overexpression facilitates neuronal differentiation in vitro, its functions in vivo, especially in the mammalian brain, and how its mutation leads to human disease pathology remains poorly understood. Here, I established the first mouse model of MYT1L Syndrome mimicking a patient specific LoF mutation. I found mice with Myt1l heterozygous mutation (Het) display MYT1L haploinsufficiency on both mRNA and protein levels and recapitulate various patient phenotypes. Utilizing this Myt1l germline knockout mouse model, I adapted Cleavage Under Targets and Release Using Nuclease (CUT&RUN) technology to map MYT1L binding targets in different developmental stages. Simultaneous measures on chromatin accessibility using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), histone modifications using CUT&RUN, and gene expression using RNA-seq revealed that MYT1L mainly functions a transcriptional repressor during mouse brain development, and its LoF leads to an upregulation of early neuronal development programs in both embryonic cortex and adult prefrontal cortex (PFC). Consequently, in the embryonic cortex, MYT1L loss results in deficient cell proliferation and precocious neuronal differentiation. In juvenile Het mouse visual cortex, neurons also show disrupted morphology and electrical properties. Furthermore, adult Het mice display abnormal cortical neuron layer specification in histology and thinner white matter in diffusion tensor imaging (DTI), and an immature neuronal transcriptional profile. This study developed a novel mouse model of MYT1L Syndrome and defined molecular and cellular functions of MYT1L during mammalian brain development, providing a useful toolkit for future pre-clinical studies of this human NDD.

Language

English (en)

Chair and Committee

Joseph J. Dougherty

Committee Members

Brian B. Clark, Harrison H. Gabel, Kristen K. Kroll, Andrew A. Yoo,

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