Identifying Genetic Loci Associated with Neurocristopathies using the Deer Mouse, Peromyscus maniculatus The neural crest is a multipotent progenitor cell type that contributes to multiple tissues throughout the body, including the peripheral nervous system, craniofacial tissues, the heart, and melanocytes. People with mutations that affect neural crest development can develop neurocristopathies, a broad class of congenital diseases that are often associated with pigmentation defects. Therefore, the rationale for this proposal is that identifying causative mutations for pigmentation defects in deer mice, Peromyscus maniculatus, will increase our knowledge of genetic lesions that can disrupt neural crest development and cause neurocristopathies. The dominant spot mutation in P. maniculatus results in a white blaze on the forehead of heterozygotes and is embryonic lethal when homozygous. The overall objective of this proposal is to capitalize on the unique features of P. maniculatus as a model system to identify the causative mutation for dominant spot. Our preliminary data show that dominant spot is linked to a 1.7 Mb interval on chromosome 20, which contains the neural crest regulatory gene Sox10. Sequencing of Sox10 exons from dominant spot homozygous embryos did not identify any sequence variants co-segregating with the phenotype, suggesting that the mutation is in a Sox10 regulatory sequence. In addition, we have found that the size of the forehead blaze varies dependent on the genetic background, suggesting the presence of modifier genes. These data have led to our central hypothesis that dominant spot results from a mutation in a regulatory region of Sox10 and that modifier genes cause variability in the dominant spot phenotype by interacting with Sox10 gene expression. This hypothesis will be tested by pursuing two specific aims. First, we will use target enrichment and high throughput sequencing to identify sequence variants associated with dominant spot. Second, a quantitative trait loci (QTL) analysis will be used to identify QTLs that are associated with the variability in spot size. This proposal is innovative because we propose to develop P. maniculatus as a model system for studying neuroscristopathies. The results from the proposed research will be significant because identifying the causative mutation for dominant spot and its genetic modifiers will increase our understanding of the neural crest gene regulatory network and provide genetic loci of clinical significance for screening in human neuroscristopathies.

Public Health Relevance

Identifying Genetic Loci Associated with Neurocristopathies using the Deer Mouse, Peromyscus maniculatus Neurocristopathies are a broad class of birth defects that are caused by mutations that affect a population of cells known as the neural crest, which migrate throughout the body and contribute to many different tissues, including the peripheral nervous system, pigment cells, craniofacial tissues, and the heart. Animals and people with white patches of skin or hair can have mutations that affect the neural crest. This proposal seeks funding to find the mutation that causes deer mice to develop a white blaze on the forehead, and is relevant to the mission of NIDCR to understand the foundational processes of neural crest formation necessary for diagnosing and treating neurocristopathies.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Small Research Grants (R03)
Project #
Application #
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Stein, Kathryn K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Carolina at Columbia
Schools of Arts and Sciences
United States
Zip Code