Thomas Gridley

Education

Ph.D., Massachusetts Institute of Technology

Biosketch

My laboratory studies genes important for embryonic development of mice, and the connections between mutations in these genes and congenital human disease syndromes. Our analyses focus on the Notch pathway, an evolutionarily conserved cell communication and signaling system, and on genes of the Snail superfamily, which encode transcriptional repressor proteins. We have created and analyzed numerous genetically engineered mouse models to understand the essential functions of individual components of these pathways. We have also generated mouse models for inherited human disease syndromes such as Alagille syndrome, and for common birth defects such as cleft palate and patent ductus arteriosus.

Research Interests

Genetic Analysis of Mouse Development and Disease

Our laboratory studies genes important for embryonic development in mice, and the connections between mutations in these genes and congenital human disease syndromes. Our analyses focus on a developmental signaling pathway termed the Notch pathway, and on genes of the Snail superfamily, which encode zinc finger transcriptional repressors.

Analysis of the Notch signaling pathway

The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism. Genes of the Notch family encode large transmembrane receptors that interact with membrane-bound ligands encoded by the Jagged (Jag1 and Jag2) and Delta-like (Dll1, Dll3, and Dll4) gene families. The signal induced by ligand binding is transmitted intracellularly by a process involving proteolytic cleavage of the receptor and nuclear translocation of the intracellular domain of the Notch protein. Notch pathway genes are essential for normal embryonic development, and mutations in genes encoding components of the Notch signaling pathway are found in several types of cancer and in three inherited disease syndromes.

We have been conducting an extensive genetic analysis of the requirements for components of the Notch signaling pathway during mouse development. We have shown that the Notch ligand encoded by the Jag1 gene plays an essential role during inner ear development. Mice with conditional deletion of the Jag1 gene in the inner ear exhibit defects in formation of all six sensory patches in the inner ear. The Jag1 gene was required by the sensory precursors, the progenitor cells that give rise to both the supporting cells and the hair cells, the sensory cells responsible for hearing. By understanding how the sensory areas develop normally, it may be possible to develop molecular tools that will aid in sensory cell regeneration in the mammalian inner ear. We have also found that certain inner ear phenotypes exhibited by Notch pathway mutants are dependent on the genetic background of the mutant mice. For example, adult mice heterozygous for the Jag1 mutation exhibit semicircular canal defects on a C3H genetic background, but not on a C57BL/6 background. We are in the processing of mapping these genetic modifiers to specific regions of the genome.

 

Analysis of Snail family genes

We are studying the roles during mouse development of genes of the Snail family. These genes are homologs of the Drosophila gene Snail, which is required for mesoderm formation during Drosophila embryogenesis. Snail family genes encode DNA binding zinc finger proteins that act as transcriptional repressors. We have made and analyzed targeted null mutations of the Snail family genes snail homolog 1 (Snai1) and snail homolog 2 (Snai2). Embryos homozygous for a null mutation of the Snai1 gene die during gastrulation, while Snai2 mutant homozygotes survive until birth. Both Snai2-/- embryos and Snai1+/- Snai2-/- double mutant embryos exhibit cleft palate, one of the most common human birth defects. Approximately 50 percent of Snai2-/- embryos exhibit cleft palate, while in Snai1+/- Snai2-/- double mutants the incidence of cleft palate increases to 100 percent. Our research indicates that cleft palate in Snai1+/- Snai2-/- embryos is due to a failure of the elevated palatal shelves to fuse.

Snail family genes are key regulators of epithelial-mesenchymal transitions in vertebrates, including the transitions that generate the mesoderm and neural crest. We have demonstrated recently that, contrary to observations in frog and avian embryos, the Snail family genes Snai1 and Snai2 are not required for formation and delamination of the neural crest in mice. However, embryos with conditional inactivation of Snai1 function exhibit defects in left-right asymmetry determination. This work demonstrates that while some aspects of Snail family gene function, such as their role in left-right asymmetry determination, appear to be evolutionarily conserved, their role in neural crest cell formation and delamination is not. This work also demonstrates that species-specific differences in the regulation of neural crest formation and migration are more profound than previously appreciated. However, the neural crest cells that are formed in Snai1/Snai2 double mutant mice are not entirely normal. While tissue-specific deletion of the Snai1 gene in neural crest cells does not cause any obvious defects, neural crest-specific Snai1 deletion on a Snai2-/- genetic background results in multiple craniofacial defects, including a cleft palate phenotype distinct from that observed in Snai1+/- Snai2-/- embryos. In embryos with neural crest-specific Snai1 deletion on a Snai2-/- background, palatal clefting results from a failure of Meckel’s cartilage to extend the mandible and thereby allow the palatal shelves to elevate. These defects are similar to those seen in humans with a disease termed the Pierre Robin Sequence.

 

Selected Publications