Tubulin Genes in Mammalian Forebrain Development

Research Inst Nationwide Children'S Hosp, Columbus OH

Investigators

Abstract

ABSTRACT Variants in tubulin genes cause many severe malformations of human forebrain development and these are called “tubulinopathies.” Multiple tubulin genes are highly expressed in the developing brain and the human genetics studies now show there is a spectrum of disease arising from tubulin mutations. Completed sequencing of multiple mammalian genomes reveals there are multiple highly similar tubulin genes. These include the genes of the TUBA1* group (TUBA1A, TUBA1B, TUBA1C) and the TUBB2* group (TUBB2A and TUBB2B). All human tubulin mutations identified to date with malformations of cortical development are de novo, heterozygous missense mutations. This suggests that a tubulin monomer protein is being produced, but acting in an inappropriate manner within the cell. We have performed the only complementary loss of function studies to date on any of the mouse Tuba1* or Tubb2* genes. A deeper understanding of the etiology of the human malformations and requirements for individual tubulin genes is essential to any therapeutics. The overall objective of this application is to understand why and how tubulin mutations cause malformations of cortical development. Our central hypothesis is that the human tubulin missense, de novo variants cause cortical malformations through dominant-negative effects on microtubule function and/or tubulin monomer protein-protein interactions. We will test this central hypothesis and accomplish the goals of this application by pursuing the following three specific aims: (1) use novel epitope-tagged alleles to determine the unique sites of expression for Tuba1 and Tubb2 genes, (2) determine cellular and embryonic molecular mechanism(s) of phenotypes caused by a series of mutations in Tuba1a/b/c, and (3) determine the unique requirements for Tubb2a and Tubb2b for mouse neural development. We expect these studies to have the following outcomes: First, we will determine for the first time the cellular expression patterns of a series of tubulin genes crucial for mammalian nervous system development. Second, we will determine the levels of genetic redundancy within the Tuba1* and Tubb2* gene families. Third, we will understand how human pathogenic mutations in tubulin genes lead to complex malformations of cortical development. By answering some of these basic questions about tubulin biology, we are poised to contemplate the best therapeutic intervention(s). Recent studies have demonstrated that treatments of cortical malformation syndromes in an already malformed brain can ameliorate some symptoms. Thus, a greater understanding of the tubulinopathy developmental disorders could open some promising doors to fruitful treatments.