Morphogenetic defects underlie Superior Coloboma, a newly identified closure disorder of the dorsal eye

Abstract

The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye. Our studies revealed the presence of the superior ocular sulcus (SOS), a transient division of the dorsal eye conserved across fish, chick, and mouse. Exome sequencing of superior coloboma patients identified rare variants in a Bone Morphogenetic Protein (Bmp) receptor (BMPR1A) and T-box transcription factor (TBX2). Consistent with this, we find sulcus closure defects in zebrafish lacking Bmp signaling or Tbx2b. In addition, loss of dorsal ocular Bmp is rescued by concomitant suppression of the ventral-specific Hedgehog pathway, arguing that sulcus closure is dependent on dorsal-ventral eye patterning cues. The superior ocular sulcus acts as a conduit for blood vessels, with altered sulcus closure resulting in inappropriate connections between the hyaloid and superficial vascular systems. Together, our findings explain the existence of superior coloboma, a congenital ocular anomaly resulting from aberrant morphogenesis of a developmental structure.

In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion is Affected by BMP

“…For a schematic depiction of the vessels see Figure 7I. A case of optic cup developmental defects impacting vascular development of the eye was also seen in the case of superior ocular coloboma [42]. There, the DRV is formed aberrantly as a result of the superior ocular sulcus, which it uses as guidance, being too deep.…”

“…These data underline the role BMP plays for RPE development but also suggest that tissue rearrangements during morphogenesis need to be considered. Moreover, defective BMP signaling was recently identified to be the cause of another morphogenetic defect of the eye-superior ocular coloboma [42]. This malformation affects the superior ocular sulcus, which can be described as a smaller dorsal optic fissure.…”

Abnormal Cone and Rod Photoreceptor Morphogenesis in gdf6a Mutant Zebrafish

“…In a previous study, we characterized the abnormal development of the ocular vasculature in gdf6a mutant eyes. 23 An insufficient vascular supply would compromise the development of photoreceptors, the most metabolically active cells of the body. 67 Although we cannot discount the possibility, the data argue against such a mechanism.…”

“…The loss of Gdf6a leads to microphthalmia, increased apoptosis, loss of dorsal markers, expansion of ventral markers, axonal misrouting, and two forms of coloboma. [20][21][22][23][24][25][26] Further, human GDF6 mutations are associated with microphthalmia, coloboma, and the photoreceptor dystrophy Leber congenital amaurosis. 24,27,28 Despite the many abnormalities of zebrafish gdf6a mutant eyes, the retinas are properly organized into three layers, and contain all expected cell types.…”

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

“…In humans, a subpopulation of colobomata is a result of mutations in developmentally important genes, however, the origins for many OF closure defects are unknown (for reviews, see (3,7,8,13,14)). Additional genes have been identified in animal models; substantial progress has been made in understanding critical processes, including growth and patterning of the ventral optic cup and optic nerve head (15- 19), cell-cell contact and signaling (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), crosstalk with migrating hyaloid precursors and extracellular matrix components (31)(32)(33)(34)(35)(36), cytoskeleton dynamics (37,38), epigenetics (39), degradation of ECM and cellular proteins (40)(41)(42), programmed cell death, survival and cell proliferation (43,44) (for reviews, see (7,8,13)). Elegant in vivo imaging studies in zebrafish and excellent anatomical analyses in chick have characterized important morphogenetic and cellular behavior (20,27,34,(45)(46)(47)(48)(49).…”