Regulation of signal-induced cytoskeletal dynamics in development and disease
Without the cytoskeleton, cells would be bags of enzymes without shape. The cytoskeleton provides structural and spatial organization for cells. However, it is the ability of cells to dynamically regulate the cytoskeleton in response to intrinsic or external signals that brings cells to life, enabling them to change morphology, polarize, migrate and assemble into complex tissues.
The goal of my laboratory is to investigate how developmental signals impinge on the cytoskeleton to orchestrate key developmental processes, as well as the related question of how dysregulation of these signaling pathways gives rise to human disease. In particular, we are investigating how extracellular cues mediated by the Wnt family of secreted growth factors can direct cytoskeletal rearrangements via Ror family cell surface receptors. This noncanonical form of Wnt signaling, which functions independently of the well-established Wnt effector beta-catenin, regulates polarized cell behaviors such as axon growth, directional migration and asymmetric cell division. Moreover, Ror mutations have been found to give rise to severe developmental abnormalities (e.g. Robinow syndrome and Brachydactyly type B) as well as various forms of metastatic cancer. However, the molecular mechanisms by which Ror receptors transmit Wnt signals to control cell polarization remain largely unclear. Using an intersectional approach combining in vivo mouse genetics and in vitro biochemical analyses, we aim to uncover new components the Wnt-Ror signaling network and characterize how these components function to link noncanonical Wnt signals to specific cytoskeletal changes. It is our hope that by studying the Wnt-Ror pathway, we will reveal novel principles of cytoskeleton regulation in both normal development and disease.
2012 Soskis MJ*, Ho HY*, Bloodgood BL, Robichaux MA, Malik A, Ataman B, Rubin AA, Zieg J, Zhang C, Shokat KM, Sharma N, Cowan CW, Greenberg ME. A chemical genetic approach reveals distinct mechanisms of EphB signaling during brain development. Nat Neurosci. Dec;15(12):1645-54.
2012 Ho HY*, Susman MW*, Bikoff JB, Ryu YK, Jonas AM, Hu L, Kuruvilla R, Greenberg ME. Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci USA. Mar 13; 109(11):4044-51
2004 Ho HY*, Rohatgi R*, Lebensohn AM, Ma, L, Lee J, Gygi SP, Kirschner MW. Toca-mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex. Cell, Jul 23; 118(2) 203.
2001 Ho HY*, Rohatgi R*, Ma L, Kirschner MW. CR16 forms a complex with N-WASP in brain and is a novel member of a conserved proline-rich actin-binding protein family. Proc Natl Acad Sci USA. Sep 25;98(20):11306-11.
2000 Rohatgi R*, Ho HY*, Kirschner MW. Mechanism of N-WASP activation by CDC42and Phosphatidylinositol 4,5-bisphosphate. J Cell Biol. Sep 18;150(6);1299-310.