Henkemeyer Lab

Research

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).

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).

Chumley MJ, Catchpole T, Silvany RE, Kernie SG, Henkemeyer M. EphB receptors regulate stem/progenitor cell proliferation, migration, and polarity during hippocampal neurogenesis. Journal of Neuroscience 27: 13481-13490 (2007).

Xu NJ, Henkemeyer M. Ephrin-B3 reverse signaling through Grb4 and cytoskeletal regulators mediates axon pruning. Nature Neuroscience 12: 268-276 (2009).

Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, Chumley MJ, Zdunek S, Wang C, Holm T, Goff SP, Pettersson S, Pestell RG, Henkemeyer M, Frisén J. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell 139: 679-692 (2009).

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).

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).

Xu NJ, Henkemeyer M. Ephrin-B3 reverse signaling through Grb4 and cytoskeletal regulators mediates axon pruning. Nature Neuroscience 12: 268-276 (2009).

These publications are available via PubMed