Tuesday, April 23, 2024
4/23/2024
ABSTRACT: Candidate and Environment: The Fuerst Lab will conduct genetic, molecular and morphological experiments related to the Aims of this proposal at the University of Idaho. The Fuerst lab team has extensive expertise centered on the cell biology and genetics of neural development. Fuerst identified Dscams as the first molecules that regulate mosaic organization of neurons and developed many of the genetic reagents for use in these experiments. Here we will build on our foundation of experience studying Dscam genes to probe the function of downstream signaling networks in neural development. Research Proposal: Developing neurons utilize a range of molecular cues to organize into neural tissues and organs. We and others have previously reported that Down syndrome cell adhesion molecule (Dscam) genes are required for normal development of neural tissues. How Dscam genes mediate a wide range of cellular responses even within a single cell type is an active area of research. In our preliminary studies we found that overexpression of Dyrk1a, whose product interacts biochemically with DSCAM, phenocopies Dscam loss of function. Further we report a redistribution of cellular DYRK1A protein in the Dscam loss of function retina and brain. Based on these observations and the genes’ known antagonistic roles in either promoting or inhibiting developmental cell death, we hypothesize that DSCAM interactions on the cell surface antagonize DYRK1A activity by controlling its subcellular localization. We test this hypothesis in two specific Aims. Aim 1: Pilot genetic studies indicate that either decreasing Dscam dosage or increasing Dyrk1a dosage results in mistargeting of retinal neuron neurites. A similar increase in Dyrk1a expression in the Ts65Dn trisomic mouse models results in a wild type targeting phenotype, however, suggesting a factor or factors in the Down syndrome critical region (DSCR) are compensating for Dyrk1a overexpression. First, we will test if increasing Dyrk1a expression in the Ts65Dn mouse model above the expression of other DSCR genes is sufficient to restore Dyrk1a overexpression neurite targeting defects (Aim 1A). Second, we will test if reducing Dscam expression in Ts65Dn mice to wild type levels restores the Dyrk1a overexpression phenotype (Aim 1B). Aim 2: We will extend our pilot study generated in retina into the brain at large. We will test if DYRK1A localization is developmentally dynamic in the brain (Aim 2A), if DSCAM regulates DYRK1A localization in the brain (Aim 2B) and if Dscam expression is sufficient to modify DYRK1A accumulation or localization in vitro (Aim 2C). Long-term goals: Our long-term goal is to understand how events at the cell surface are transduced to generate different cellular responses. This R03 will facilitate completion and publication of a pilot study, the results of which will inform experiments to understand how regulation of DYRK1A localization impacts its function in development and disease. Significance: Understanding why mutation or overexpression of genes involved in neural development can present with a variety of signs and symptoms in people will require us to also understand the functions of the affected genes with the long-term goal of developing clinical interventions. Here we explore the interaction between two interacting genes in the Down Syndrome critical region, relevant to studies and treatments focusing on either single gene. Understanding the downstream signaling pathways utilized by surface receptors will be essential to help scientists and clinicians pinpoint strategies to treat human diseases.
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