Notch and BMP Signaling Ligands in Ocular Development: AnAnalysis of Altered Spatiotemporal Expression and GeneDosage
2020
Ocular development requires precise interactions
between the neuroepithelium, surface ectoderm, mesoderm, and neural
crest-derived cells. By way of physical and chemical contact with
one another, these cell types work in concert throughout embryonic
and early postnatal development to form the multiple, specialized
tissues of the eye. Abnormalities in ocular tissue morphogenesis
can lead to congenital diseases of both the anterior and posterior
eye. Two genes encoding ligands within the Notch and Bone
Morphogenic Protein (BMP) signaling pathways, Jag1 and Bmp4,
respectively, have been implicated in ocular dysgenesis. However,
their precise spatiotemporal requirements in eye development are
undefined. The trabecular meshwork (TM) is a tiny tissue
responsible for the majority of aqueous humor drainage in the front
of the eye, and thus regulates intraocular pressure. Previous
literature has shown that single heterozygous null mutations of
Jag1 and Bmp4 result in TM hypoplasia, yet the timing and
underlying mechanisms causing this developmental dysgenesis are
unknown. Surprisingly, the cellular mechanisms driving normal TM
formation are also poorly understood. To thoroughly examine both
wild-type as well as Jag1+/– and Bmp4+/– mice, I assessed tissue
morphology, cellular proliferation, apoptotic cell death, and
markers for TM differentiation over the full time course of TM
development. I found that postnatal day 1 marks an important stage
in TM cellular differentiation, yet the phenotypic abnormalities
detected in adult Jag1 +/– and Bmp4+/– mice do not arise until
later stages. In order to determine the tissue-specific
requirements of JAG1 and BMP4 during early ocular development, I
next examined multiple genetically modified mouse strains in which
these genes were conditionally deleted at specific early time
points in the optic cup of the mouse eye. Previous studies had
established that both ligands are expressed in the margins of the
optic cup during embryogenesis, a position consistent with reported
anterior eye defects in the heterozygotes. Surprisingly,
morphological, molecular, and functional analysis revealed that
both Jag1 and Bmp4 are dispensable for ocular development when
individually removed from the optic cup neuroepithelium. These
results indicate that this important signaling occurs outside of
the optic cup spatially and/or temporally during early eye
development. Together, these data demonstrate the complexity of
spatiotemporal expression patterns and gene dosage effects of Jag1
and Bmp4 throughout ocular development. This work has provided
novel insight into the molecular mechanisms underlying early eye
morphogenesis and malformation.
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