Loss of adenomatous polyposis coli (apc) results in an expanded ciliary marginal zone in the zebrafish eye

Abstract

The distal region of neural retina (ciliary marginal zone [CMZ]) contains stem cells that produce non-neural and neuronal progenitors. We provide a detailed gene expression analysis of the eyes of apc mutant zebrafish where the Wnt/b-catenin pathway is constitutively active. Wnt/b-catenin signaling leads to an expansion of the CMZ accompanied by a central shift of the retinal identity gene sox2 and the proneural gene atoh7. This suggests an important role for peripheral Wnt/b-catenin signaling in regulating the expression and localization of neurogenic genes in the central retina. Retinal identity genes rx1 and vsx2, as well as meis1 and pax6a act upstream of Wnt/b-catenin pathway activation. Peripheral cells that likely contain stem cells can be identified by the expression of follistatin, otx1, and axin2 and the lack of expression of myca and cyclinD1. Our results introduce the zebrafish apc mutation as a new model to study signaling pathways regulating the CMZ.

Wnt Signaling Promotes Müller Cell Proliferation and Survival after Injury

“…18 In lower vertebrates, Wnt pathway stimulation results in the expansion of an RPC population in the ciliary marginal zone (CMZ). [19][20][21][22][23] Conversely, Wnt pathway inhibition depletes CMZ progenitors. 21,24,25 A variety of Wnt reporter mice have been used to identify sites of Wnt signaling in the mammalian retina, with conflicting results.…”

Continued growth and circuit building in the anamniote visual system

“…For example, constitutive upregulation of Wnt/b-catenin signaling in homozygous null adenomatous polyposis coli (apc) mutants leads to an expanded population of proliferating progenitors within the CMZ. The increase in proliferating progenitors does not lead to an increase in retinal size, most likely because apc mutant retinae also exhibit increased apoptosis (Stephens et al, 2010). In addition, apc embryos have a smaller, unorganized tectum (Varga, unpublished data), suggesting that perturbation of Wnt/b-catenin signaling may negatively impact proliferation and differentiation in the optic tectum either through its cell-cycle-linked functions (Davidson et al, 2009).…”

Wnt Signaling and Injury Repair

“…Likewise, blocking Wnt signaling after amputation of the dorsal fin in zebrafish impairs their normal fin regeneration (Kawakami et al 2006). Inhibiting Wnt signaling in the eyes of animals with continually regenerating retinas results in an abrupt cessation in this regenerative ability (Kubo et al 2003;Cho and Cepko 2006;Stephens et al 2010;Ramachandran et al 2011).…”

“…The early consensus seems to be that Wnt signaling blockade disrupts the recruitment of stem/progenitor cells to the injury site (Liu et al 2007b;Das et al 2008;Denayer et al 2008;Stephens et al 2010;Ramachandran et al 2011) and adversely affects the proliferative phase of the healing process (Qyang et al 2007;Stoick-Cooper et al 2007). The formation of a blastema, the mass of multipotent cells at the tip of the wounded limb (Bryant et al 2002), depends upon recruitment and proliferation (Agata et al 2007).…”