Value Proposition
· Novel loss-of-function mutations: Three distinct ENU-induced point mutations (Sema3A^K108N, Sec24b^Y613X, and Megf8^L1775P) that create specific loss-of-function phenotypes while maintaining protein expression and secretion
· Validated genetic models: Each strain has been thoroughly characterized and phenotypically validated to recapitulate known null phenotypes, providing reliable research tools
· Mechanistic insights: The Sema3A^K108N mutation uniquely separates receptor binding from downstream signaling, allowing researchers to study signaling mechanisms independent of receptor interaction
· Multiple research applications: Models are valuable for studying peripheral nervous system development, neural tube closure defects, planar cell polarity, axon guidance, and BMP4 signaling pathways
Unmet Need
Research into peripheral nervous system development, neural tube closure, and axon guidance currently relies on complete knockout models that eliminate entire gene functions, limiting the ability to study specific protein domains and signaling mechanisms. Traditional null mutants often cause embryonic lethality or severe phenotypes that can mask subtle developmental processes and prevent detailed mechanistic analysis. These approaches make it difficult to understand how individual amino acid residues contribute to protein function and to identify potential therapeutic targets for developmental disorders. Therefore, there is a need for genetic models with specific point mutations to address mechanistic questions in neuronal development and guidance.
Technology Description
Researchers at Johns Hopkins have developed three mouse strains carrying ENU-induced point mutations for studying peripheral nervous system development and related disorders. The mutations affect Sema3A (K108N), Sec24b (Y613X), and Megf8 (L1775P) genes, each critical for different aspects of neuronal development. The Sema3A mutation affects axon guidance while maintaining receptor binding, the Sec24b mutation disrupts protein trafficking leading to neural tube defects, and the Megf8 mutation impairs BMP4 signaling causing developmental abnormalities. These models reproduce null phenotypes while enabling mechanistic studies of specific protein functions in neuronal development, neural tube closure, and axon guidance.
Stage of Development
· These mutant mouse strains are available on Jax Lab’s repository:
o Jax# 014646 C3.B6-Sema3am808Ddg/J
o Jax# 014645 C3.B6-Sec24bY613X/J
o Jax# 025418 C3;B6-Megf8m687Ddg/J
Data Availability
· n/a
Publications
· Janna Merte, Qiang Wang, Craig W. Vander Kooi, Sarah Sarsfield, Daniel J. Leahy, Alex L. Kolodkin, David D. Ginty. A Forward Genetic Screen in Mice Identifies Sema3AK108N, which Binds to Neuropilin-1 but Cannot Signal. Journal of Neuroscience 21 April 2010, 30 (16) 5767-5775; DOI: 10.1523/JNEUROSCI.5061-09.2010
· Merte, J., Jensen, D., Wright, K. et al. Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure. Nat Cell Biol 12, 41–46 (2010). https://doi.org/10.1038/ncb2002
· Caitlin Engelhard, Sarah Sarsfield, Janna Merte, Qiang Wang, Peng Li, Hideyuki Beppu, Alex L Kolodkin, Henry M Sucov, David D Ginty (2013) MEGF8 is a modifier of BMP signaling in trigeminal sensory neurons eLife 2:e01160
