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A forward genetic screen in mice identifies Sema3A(K108N), which binds to neuropilin-1 but cannot signal.


We have performed a three-generation, forward genetic screen to identify recessive mutations that affect the patterning of the peripheral nervous system. Using this assay, we identified Sema3A(K108N), a novel loss-of-function allele of Sema3A. Class 3 semaphorins, which include Sema3A, are structurally conserved secreted proteins that play critical roles in the development and function of the nervous system. Sema3A(K108N) mutant mice phenocopy Sema3A-null mice, and Sema3A(K108N) protein fails to repel or collapse DRG axons in vitro. K108 is conserved among semaphorins, yet the loss-of-function effects associated with K108N are not the result of impaired expression, secretion, or binding of Sema3A to its high-affinity receptor Neuropilin-1 (Npn-1). Using in silico modeling and mutagenesis of other semaphorin family members, we predict that Sema3A(K108N) interacts poorly with the Npn-1/PlexA holoreceptor and, thus, interferes with its ability to signal at the growth cone. Therefore, through the use of a forward-genetic screen we have identified a novel allele of Sema3A that provides structural insight into the mechanism of Sema3A/Npn-1/PlexinA signaling.

Pubmed ID: 20410128


  • Merte J
  • Wang Q
  • Vander Kooi CW
  • Sarsfield S
  • Leahy DJ
  • Kolodkin AL
  • Ginty DD


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

April 21, 2010

Associated Grants

  • Agency: NCRR NIH HHS, Id: P20 RR020171
  • Agency: NCI NIH HHS, Id: R01 CA090466
  • Agency: NIGMS NIH HHS, Id: R01 GM099321
  • Agency: NIMH NIH HHS, Id: R01 MH059199
  • Agency: NIMH NIH HHS, Id: R01 MH059199-10
  • Agency: NIMH NIH HHS, Id: R01 MH59199
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Asparagine
  • Cell Line
  • Female
  • Genes, Recessive
  • Genetic Testing
  • Humans
  • Lysine
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Neuropilin-1
  • Point Mutation
  • Protein Binding
  • Semaphorin-3A
  • Signal Transduction