Abstract
Coloboma, a congenital disorder characterized by gaps in ocular tissues,
is caused when the choroid fissure fails to close during embryonic
development. Several loci have been associated with coloboma, but these
represent less than 40% of those that are involved with this disease.
Here, we describe a novel coloboma-causing locus, BMP3. Whole exome
sequencing and Sanger sequencing of patients with coloboma identified
three variants in BMP3, two of which are predicted to be disease
causing. Consistent with this, bmp3 mutant zebrafish have aberrant
fissure closure. bmp3 is expressed in the ventral head mesenchyme and
regulates phosphorylated Smad3 in a population of cells adjacent to the
choroid fissure. Furthermore, mutations in bmp3 sensitize embryos to
Smad3 inhibitor treatment resulting in open choroid fissures. Micro CT
scans and Alcian blue staining of zebrafish demonstrate that mutations
in bmp3 cause midface hypoplasia, suggesting that bmp3 regulates cranial
neural crest cells. Consistent with this, we see active Smad3 in a
population of periocular neural crest cells, and bmp3 mutant zebrafish
have reduced neural crest cells in the choroid fissure. Taken together,
this data suggests that Bmp3 controls Smad3 phosphorylation in neural
crest cells to regulate early craniofacial and ocular development.