Roles for mRNA Regulation in Mammalian Brain Development and Neurodevelopmental Disorders

Silver, Debra L

Lennox, Ashley

2018-09-21T16:08:42Z

2022-08-30T08:17:14Z

2018

Genetics and Genomics

The cerebral cortex is an anatomically complex brain structure that controls our higher cognitive functions such as abstract thought and language. The cortex is largely shaped during embryonic development when radial glial progenitors divide and differentiate to produce neurons. Neurons are organized into 6-layers through migration guided by the structural support of radial glial cells. Disruptions in progenitor proliferation or neuronal migration underly diverse neurodevelopmental disorders with life-long impacts on cognitive, psychiatric, and motor functions. Developmental mechanisms that build the brain are regulated by precise gene-expression networks. Here, we uncover two novel layers of post-transcriptional mRNA regulation in the developing cortex. First, we used model models to describe a widespread phenomenon of mRNA localization to the distal structures—the basal process and endfeet—of radial glial progenitors. With live imaging approaches, we detected active mRNA transport to and local translation within radial glial endfeet. Transcriptomic and proteomic analyses revealed that endfeet contain cytoskeletal, signaling, and proteostasis factors that may be locally and dynamically controlled. The second line of investigation focused on the RNA-helicase DDX3X which is frequently mutated in neurodevelopmental disorders. We discovered that Ddx3x is required both in progenitor differentiation and neuronal migration in the developing mouse cortex. DDX3X mutations varied from loss-of-function to missense alleles, and a subset of missense variants caused severe cortical malformations in patients. Biochemical and cell biological assays revealed that dominant missense mutations reduced DDX3X helicase activity and induced formation of RNA-protein aggregates associated with impaired translation, uncovering novel pathologies underlying developmental disorders. Together, these studies extend our understanding of post-transcriptional regulation in brain development and neurodevelopmental disorders.

https://hdl.handle.net/10161/17491

Developmental biology

Neurosciences

Genetics

cortical development

DDX3X

mRNA regulation

Translation

Roles for mRNA Regulation in Mammalian Brain Development and Neurodevelopmental Disorders

Dissertation

48