Pax6 organizes the anterior eye segment by guiding two distinct neural crest waves

Abstract

Cranial neural crest (NC) contributes to the developing vertebrate eye. By multidimensional, quantitative imaging, we traced the origin of the ocular NC cells to two distinct NC populations that differ in the maintenance of sox10 expression, Wnt signalling, origin, route, mode and destination of migration. The first NC population migrates to the proximal and the second NC cell group populates the distal (anterior) part of the eye. By analysing zebrafish pax6a/b compound mutants presenting anterior segment dysgenesis, we demonstrate that Pax6a/b guide the two NC populations to distinct proximodistal locations. We further provide evidence that the lens whose formation is pax6a/b-dependent and lens-derived TGFβ signals contribute to the building of the anterior segment. Taken together, our results reveal multiple roles of Pax6a/b in the control of NC cells during development of the anterior segment.

The Ocular Neural Crest: Specification, Migration, and Then What?

“…Fate mapping studies in mice have shown that both NC and mesoderm contribute to the corneal stroma and corneal endothelium, while in chick, both of these corneal structures as well as the iris stroma are NC derived ( Gage et al, 2005 ). Time-lapse imaging of pre- and post-migratory NC cells in zebrafish embryos has shown at least three waves, including two distinct Sox10 - positive and one Foxd3-positive cell populations ( Eason et al, 2017 ; Takamiya et al, 2020 ). Sox10-positive cells migrate early after optic cup formation and preliminary fate mapping studies show minimal contributions to the adult eye (unpublished data).…”

“…Animal models have shown that Pax6 targets essential extracellular signaling molecules that control multiple steps in eye morphogenesis ( Cvekl and Callaerts, 2017 ). Pax6 is initially expressed in the optic pit and subsequently in the optic vesicle, optic stalk and overlying surface ectoderm ( Enwright and Grainger, 2000 ; Grocott et al, 2011 ; Cvekl and Callaerts, 2017 ; Takamiya et al, 2020 ). Pax6 is important for optic stalk formation and retinal differentiation, which correlates with optic nerve and foveal hypoplasia observed with human Pax6 gene mutations.…”

“…Further, during cup morphogenesis, Pax6 expression is primarily restricted to the surface ectoderm and the distal end of the optic cup. This expression underpins formation of the lens placode and subsequent detachment of the lens from the cornea ( Takamiya et al, 2020 ) and helps to explain the relationship between Pax6 mutations and PA. Notably, Pax6 gene mutations and deletions yield phenotypic differences between humans and animal models.…”

Genetics Underlying the Interactions between Neural Crest Cells and Eye Development

“…In zebrafish, sox10 continues to be expressed within the mandibular and maxillary cartilage during the early larval stage but is absent in juveniles [ 11 ]. While sox10 positive cells enter into the developing eye, its expression is short-lived and it is unclear to which ocular tissues these neural crest cells contribute [ 11 , 32 ]. In humans, autosomal dominant nonsense and frame shift mutations in SOX10 , are associated with Waardenburg syndrome, which is primarily characterized by pigmentation abnormalities and mild facial dysmorphism [ 151 , 152 ].…”

“…In zebrafish, neural crest cells migrate in at least three waves. Recent studies have shown that there are two distinct sox10 -positive cell populations that migrate into the eye 12–18 h after neural crest delamination and a subsequent foxd3 -positive cell population that migrates into the anterior segment in the late embryonic and early larval stages [ 11 , 32 ]. Following migration into the anterior segment, signals that regulate terminal neural crest cell differentiation are less well-understood and additional work is needed to identify these gene regulatory networks [ 33 , 34 ].…”