These Megf8 mutant mice carry a chemically-induced L1775P (leucine to proline) mutation that causes embryonic lethality involving pre-axial polydactyly, skeletal defects, disruption of left-right patterning, and severe heart defects.
David D. Ginty, Harvard Medical School
Megf8 (multiple EGF-like-domains 8) is widely expressed during early embryonic development with strong expression in the somites, limb buds, primordial gut, developing eye, and pharyngeal arches. Throughout embryogenesis and into the postnatal period, MEGF8 is present in the sensory neurons of the dorsal root ganglion and trigeminal ganglion, as well as the central nervous system including the developing neuroepithelium, postnatal hippocampus, layer 4/5 of the cortex and the olfactory bulb. Megf8 has been identified as a novel modifier of BMP4 (bone morphogenetic protein 4) signaling in trigeminal ganglion (TG) neurons. TG axon growth is robustly inhibited by
BMP4, and this inhibition is dependent on MEGF8 expression.
This mutant strain carries a chemically-induced loss-of-function L1775P (leucine to proline) mutation of the mouse Megf8 gene. Heterozygotes are viable and fertile with no overt phenotype, but homozygotes die by embryonic day 16.5 (E16.5). The mutation leads to pre-axial polydactyly, skeletal defects, disruption of left-right patterning, and severe heart defects. Homozygous embryos exhibit severe defasciculation of the ophthalmic branch of the trigeminal nerve, have a split sternum and show delayed ossification of the rib cage. Complete left-right inversion of heart looping is also seen.
Male C57BL/6 mice were treated with multidose N-ethyl-N-nitrosourea (ENU) and then bred to C3H/He females. The resulting male pups were then bred to C3H/He females to obtain second generation mice. The resulting female offspring were subsequently bred back to their parental line to obtain third generation mice. A mutagenesis screen was then performed to select mice with mutations effecting peripheral nervous system patterning. A forward-genetic screen approach found a mutation in Megf8. Sequencing of this gene identified founder Line 687 with a T to C transition on chromosome 7 between rs3715453 and D7JHMI24 which encodes a single leucine to proline substitution in the fourth Kelch domain of Megf8 resulting in a loss-of-function mutation (L1557P).
|Allele Name||mutation 687, David D Ginty|
|Allele Type||Chemically induced (ENU)|
|Gene Symbol and Name||Megf8, multiple EGF-like-domains 8|
|Strain of Origin||C57BL/6|
|Molecular Note||ENU mutagenesis induced a T to C point mutation that results in the amino acid substitution of proline for lysine at position 1775 (L1775P) in the fourth Kelch domain.|
Heterozygotes are viable and fertile. Homozygotes die in utero by embryonic day 16.5 (E16.5).
When using the C3;B6-Megf8m687Ddg/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #025418 in your Materials and Methods section.