Unidirectional Eph/ephrin signaling creates a cortical actomyosin differential to drive cell segregation.
Cell segregation is the process by which cells self-organize to establish developmental boundaries, an essential step in tissue formation. Cell segregation is a common outcome of Eph/ephrin signaling, but the mechanisms remain unclear. In craniofrontonasal syndrome, X-linked mosaicism for ephrin-B1 expression has been hypothesized to lead to aberrant Eph/ephrin-mediated cell segregation. Here, we use mouse genetics to exploit mosaicism to study cell segregation in the mammalian embryo and integrate live-cell imaging to examine the underlying cellular and molecular mechanisms. Our data demonstrate that dramatic ephrin-B1-mediated cell segregation occurs in the early neuroepithelium. In contrast to the paradigm that repulsive bidirectional signaling drives cell segregation, unidirectional EphB kinase signaling leads to cell sorting by the Rho kinase-dependent generation of a cortical actin differential between ephrin-B1- and EphB-expressing cells. These results define mechanisms of Eph/ephrin-mediated cell segregation, implicating unidirectional regulation of cortical actomyosin contractility as a key effector of this fundamental process.
Department of Cell and Tissue Biology, Program in Craniofacial Biology and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143.
Audrey K
http://orcid.org/0000-0003-4760-4613
AK
O'Neill
Department of Cell and Tissue Biology, Program in Craniofacial Biology and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143.|Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143.
Abigail A
AA
Kindberg
Department of Cell and Tissue Biology, Program in Craniofacial Biology and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143.|Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143.
Terren K
TK
Niethamer
Department of Cell and Tissue Biology, Program in Craniofacial Biology and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143.
Andrew R
http://orcid.org/0000-0003-4164-5801
AR
Larson
Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Davis, CA 95817.|Department of Neurobiology, Harvard Medical School, Boston, MA 02115.
Hsin-Yi Henry
http://orcid.org/0000-0002-8780-7864
HH
Ho
Department of Neurobiology, Harvard Medical School, Boston, MA 02115.
Michael E
http://orcid.org/0000-0003-1380-2160
ME
Greenberg
Department of Cell and Tissue Biology, Program in Craniofacial Biology and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143 jeffrey.bush@ucsf.edu.|Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143.|Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143.
Jeffrey O
http://orcid.org/0000-0002-6053-8756
JO
Bush
D000199:Actins / Q000378:metabolism; D000205:Actomyosin / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D036387:Ephrin-B1 / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D046569:Neuroepithelial Cells / Q000166:cytology* / Q000378:metabolism; D036081:Receptors, Eph Family / Q000378:metabolism*; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism
D000199:Actins; D036387:Ephrin-B1; D049452:Green Fluorescent Proteins; D000205:Actomyosin; D036081:Receptors, Eph Family; D054460:rho-Associated Kinases