The primary goal of my laboratory is to understand the biochemical signals that regulate cell-cell interactions during embryonic development. We focus on a large group of transmembrane receptor tyrosine kinases known as the Eph receptors and their activating ligands, which are termed Ephrins. The Ephrin ligands are also membrane-anchored and we now know that they too are able to act like a receptor to transduce signals into their own cell. Thus, when a cell expressing an Eph receptor contacts a cell expressing an Ephrin ligand, novel bidirectional signals are transduced into both the Eph receptor-expressing cell (forward signaling) and the Ephrin ligand-expressing cell (reverse signaling). In general, Eph-Ephrin bidirectional signals are known to regulate contact-mediated repulsion-type cellular movements such as those utilized by the axon growth cone during neural pathfinding.
Key to our studies is the generation of Eph and Ephrin knockout mutant mice using embryonic stem cell technologies. Our phenotypic analysis of these mutant mice demonstrates that forward and reverse signaling is important for nerve axon pathfinding and synaptogenesis as the developing brain and spinal cord become wired. Our studies also show diverse roles for Ephs and Ephrins in regulating cell-cell interactions outside of the nervous system, for instance during the development of embryonic midline structures and as blood vessels form and remodel to form the vascular network. These mice have also allowed us to uncover functions for Ephs and Ephrins in the adult, including important roles in the vestibular system and in the regulation of neuronal and intestinal stem cells.
In addition to a developmental genetic approach, our ongoing analysis of Eph-Ephrin bidirectional signaling also involves in vitro biochemical, cell-based, and live-cell imaging studies to characterize in detail how the forward and reverse signals are transduced into the cell. Consistent with cell migration/adhesion and axon pathfinding defects observed in knockout mice, our biochemical and cellular studies indicate that forward and reverse signaling can induce a variety of cytoskeletal responses, including the disassembly of F-actin stress fibers and focal adhesions leading to, for example, growth cone collapse and axonal repulsion. Such cellular responses are consistent with the ability of the Ephs and Ephrins to form protein-protein interactions with a number of molecules with known roles in cytoskeletal regulation.
By combining in vivo biological studies of mutant mice with in vitro biochemical and cell-based approaches, our aim is to better understand the molecular basis by which cellular movements and cell-cell interactions are regulated as the embryo develops and in the adult.
RECENT PUBLICATIONS
Williams SE, Mann F, Sakurai T, Erskine L, Wei S, Rossi DJ, Gale NW, Holt CE, Mason CA, Henkemeyer M, "Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm" Neuron, 39:919-935, 2003
Henkemeyer, M, Itkis OS, Ngo M, Hickmott PW, Ethell IM, "Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus" J. Cell Biol., 163:1313-1326, 2003
Cowan CA, Yokoyama N, Saxena A, Chumley MJ, Silvany RE, Baker LA, Srivastava D, Henkemeyer M, "Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development" Developmental Biology, 272:263-271, 2004
Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, Shay J, Baker LA, Henkemeyer M, "Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development" Developmental Biology, 271:272-290, 2004
Dravis, C., Wu, T., Chumley, M.J., Yokoyama, N., Wei, S., Wu, D.K., Marcus, D.C. and Henkemeyer, M, "EphB2 and ephrin-B2 regulate the ionic homeostasis of vestibular endolymph" Hearing Research, 223:93-104, 2007
SIGNIFICANT PUBLICATIONS
Henkemeyer M, Orioli D, Henderson JT, Saxton TM, Roder J, Pawson T, Klein R, "Nuk controls pathfinding of commissural axons in the mammalian central nervous system" Cell, 86:35-46, 1996
Holland S, Gale N, Mbamalu G, Yancopoulos G, Henkemeyer M, Pawson T, "Bidirectional signaling through the Eph family receptor Nuk and its transmembrane ligands" Nature, 383:722-725, 1996
Cowan CA, Yokoyama N, Bianchi LM, Henkemeyer M, Fritzsch B, "EphB2 guides axons at the midline and is necessary for normal vestibular function" Neuron, 26:417-430, 2000
Yokoyama N, Romero MI, Cowan CA, Galvan P, Helmbacher F, Charnay P, Parada LF, Henkemeyer M, "Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline" Neuron, 29:85-97, 2001
Cowan CA, Henkemeyer M, "The SH2/SH3 adaptor protein Grb4 transduces B-ephrin reverse signals" Nature, 413:174-179, 2001
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