OHSU

Heart and Smooth Muscle Development in Drosophila and Mice

This lab studies heart and smooth muscle development in Drosophila and mice. We take advantage of the power of developmental genetics in Drosophila and evolutionary conservation of developmental mechansims to understand mammalian organogenesis. We have developed a method to identify targets of transcriptional regulation by the homeodomain protein Tinman. Tinman is a conserved determinant of cardiogenesis. Homozygous fly mutants have no heart or smooth muscle. Heterozygous human mutants have been identified with a broad spectrum of congenital heart lesions.

We identified a novel, secreted signaling protein called Jelly belly (Jeb) as a target of Tinman regulation. In jeb mutants no mature smooth muscles develop. Smooth muscle precursors are normally specified but they fail to migrate and differentiate. Jeb is synthesized in cells immediately adjacent to the smooth muscle precursors, secreted from them and taken up by the smooth muscle precursors.

We have recently identified a high affinity receptor for Jeb that belongs to the insulin receptor superfamily. It is the Drosophila homologue of the human proto-oncogene Anaplastic Lymphoma Kinase. The normal function of this receptor has been unknown. We are performing mutagenesis experiments to determine the mechanism of ligand binding and receptor activation. The identification of this receptor as the Jeb receptor makes clear that this signaling system is conserved in mammals as well. We are exploiting this conservation to extend our work on Jeb signaling in Drosophila to mammalian development and disease.