Abstract
Forward
genetic screens with ENU (N-ethyl-N-nitrosourea) mutagenesis can
facilitate gene discovery, but mutation identification is often
difficult. We present the first study in which an ENU-induced mutation
was identified by massively parallel DNA sequencing. This mutation
causes heterotaxy and complex congenital heart defects and was mapped to
a 2.2-Mb interval on mouse chromosome 7. Massively parallel sequencing
of the entire 2.2-Mb interval identified 2 single-base substitutions,
one in an intergenic region and a second causing replacement of a highly
conserved cysteine with arginine (C193R) in the gene Megf8. Megf8 is
evolutionarily conserved from human to fruit fly, and is observed to be
ubiquitously expressed. Morpholino knockdown of Megf8 in zebrafish
embryos resulted in a high incidence of heterotaxy, indicating a
conserved role in laterality specification. Megf8(C193R) mouse mutants
show normal breaking of symmetry at the node, but Nodal signaling failed
to be propagated to the left lateral plate mesoderm. Videomicroscopy
showed nodal cilia motility, which is required for left-right
patterning, is unaffected. Although this protein is predicted to have
receptor function based on its amino acid sequence, surprisingly
confocal imaging showed it is translocated into the nucleus, where it is
colocalized with Gfi1b and Baf60C, two proteins involved in chromatin
remodeling. Overall, through the recovery of an ENU-induced mutation, we
uncovered Megf8 as an essential regulator of left-right patterning.
https://link.springer.com/article/10.1186/1471-2105-4-42
Tästä saa fylogeneettisen tiedon. BTB Kelch domeeniproteiineista.
(https://ghr.nlm.nih.gov/gene/MEGF8
Uusimpia artikkeleita lokakuulta 2019)
https://link.springer.com/article/10.1186/1471-2105-4-42
Tästä saa fylogeneettisen tiedon. BTB Kelch domeeniproteiineista.
(https://ghr.nlm.nih.gov/gene/MEGF8
Uusimpia artikkeleita lokakuulta 2019)
The MEGF8
gene provides instructions for making a protein whose function is
unclear. Based on its structure, the Megf8 protein may be involved in
cell processes such as attaching cells to one another (cell adhesion)
and helping proteins interact with each other. Researchers also suspect
that the Megf8 protein plays a role in the normal shaping (patterning)
of many parts of the body during embryonic development.
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