4115 McGaugh Hall
University of California Irvine
Irvine, CA 92697
Tel: (949) 824-9798
Fax: (949) 824-4709
Website: Lab Homepage
Molecular genetic analysis of nuclear migration and growth factor signaling in Drosophila
We use Drosophila genetics, molecular and cellular techniques to study three mechanisms critical for normal development: (1) How extracellular proteoglycans (HSPGs) affect growth factor (especially BMP) signaling (2) How cells respond transcriptionally to Bone Morphogenetic Protein (BMP) ligands and (3) How a genetic pathway regulates the position and movement of the nucleus within a cell. The genes and pathways involved in these processes are evolutionarily conserved, and when disrupted in humans, cause congenital defects and disease.
Proteoglycans in development: HSPGs are extracellular macromolecules found on virtually every cell in eumetazoans. They are composed of a core protein covalently linked to long unbranched stretches of repeating glycosaminoglycan (GAG) sugar chains that bind and modulate the signaling efficiency of many growth factor ligands. In humans mutations that affect HSPG function are implicated in developmental defects and cancer. We have found that in flies, activity of the GAG chain co-polymerases EXT1 (Ttv) and EXT2 (Sotv) is required for BMP, Wg and Hh signaling. More recently we showed that GAG synthesis is developmentally regulated through a novel translational control mechanism that we are now trying to understand.
Transcriptional response to BMPs: For several years we have studied Schnurri (Shn), a zinc finger DNA-binding protein cloned and characterized in collaboration with Dr. Kavita Arora that enables cells to respond to BMP signals. Shn is essential for BMP signaling in Drosophila and is homologous to the human transcription factors Shn1, Shn2 and Shn3. We have found that Shn interacts with the BMP-specific Smad, Mad, in response to BMP pathway activation and can mediate either transcriptional activation or repression depending on the cellular context. Interestingly, we found that the human ortholog Shn1, can also act in BMP signaling in vertebrates, and does so by binding to very similar cis-elements. We continue to use genetic, molecular and mathematical approaches to study the role of Shn in BMP signaling.
Nuclear migration: In most differentiated cells the nucleus is usually present at a defined subcellular position and maintained there through an active process that is not well understood. We have characterized two genes, Drosophila nudC (DnudC), and Drosophila Lissencephaly1 (DLis1) that are critical components of an evolutionarily conserved pathway regulating nuclear migration. These genes act by affecting the activity of the minus-end directed microtubule motor cytoplasmic dynein. Mutations in the human Lis1 homolog cause a birth defect Miller-Dieker Lissencephaly. This syndrome results from failure of embryonic neuronal migration, suggesting a link between nuclear and neuronal movement. We are currently focused (i) understanding the link between DLis1 and the motor complex in nuclear migration, (ii) identifying other genes in the nuclear migration pathway that may play regulatory or structural roles.