A forward genetic screen in mice identifies Sema3AK108N, which binds to Neuropilin-1 but cannot signal

Janna Merte, Qiang Wang, Craig W. Vander Kooi, Sarah Sarsfield, Daniel J. Leahy, Alex L. Kolodkin, David D. Ginty

Research output: Contribution to journalArticlepeer-review

Abstract

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 Sema3AK108N, 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. Sema3AK108N mutant mice phenocopy Sema3A-null mice, and Sema3AK108N 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 Sema3AK108N 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. Copyright

Original languageEnglish (US)
Pages (from-to)5767-5775
Number of pages9
JournalJournal of Neuroscience
Volume30
Issue number16
DOIs
StatePublished - Apr 21 2010

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'A forward genetic screen in mice identifies Sema3A<sup>K108N</sup>, which binds to Neuropilin-1 but cannot signal'. Together they form a unique fingerprint.

Cite this