Lab Overview

The focus of my laboratory’s research is to understand how growth and differentiation in the mammalian embryo is regulated. This process is truly remarkable if you consider that an undifferentiated embryonic cell placed in the context of the embryo will divide and differentiate in accord with the host embryo while an embryonic cell grafted under the skin of a nude mouse will develop into a tumor. To begin to understand the genetic basis for the normal control of development, my laboratory has taken advantage of a classical set of overlapping chromosomal deletions in mouse (1). Within the deletion complex, we have focused on three essential genes required for: mesoderm induction (mesd) (2,5), neuroendocrine lineage development (Arnt2) (3,4), and development of a subset of tissues derived in part from the cardiac neural crest (carnc) (6).

Mesd is required for control of cell proliferation, embryonic patterning and mesoderm differentiation. Within the mesd critical region, we have identified two novel candidate genes (7). Partial sequence of the mesd candidate-1 transcript identified a 132 AA domain with similarity to the leucine rich region of the adenomatous polyposis coli (APC) protein. Similar domains are also observed in b-catenin, armadillo, and nuclear docking proteins. The mesd candidate-2 gene encodes a predicted 362 AA protein related to a domain located in the central region of the talin protein. To determine which locus is responsible for the mesd defects and identify roles for these proteins throughout development, we are characterizing embryonic expression patterns, subcellular localization, and evaluating BAC transgenics. The mesd critical region overlaps with a region of human chromosome 15 implicated in a syndrome of tapetoretinal degeneration, mental retardation and spasticity (TD/MR/S) and a second syndrome causing autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Future studies will focus on identification of mesd interacting factors and lineage specific targeted disruption of mesd.

In contrast to the early requirement for mesd, we determined that Arnt2, a member of the bHLH-PAS family of transcriptional regulators is required for development of the neuroendocrine lineage in the hypothalamus (4). We continue to investigate the fate of the neuroendocrine lineage as well as examine homozygous neonates for additional defects associated with loss of Arnt2. Finally, recent phenotypic studies suggest that a new functional region required for development of derivatives of the cardiac neural crest (carnc) map within the deletions. Future studies will focus on continued phenotypic analysis, fine mapping this locus, and identification of candidate genes.

REFERENCES


RELATED REVIEW ARTICLES