Negative and positive auto-regulation of BMP expression in early eye development

Abstract

Previous results have shown that Bone Morphogenetic Protein (BMP) signaling is essential for lens specification and differentiation. How BMP signals are regulated in the prospective lens ectoderm is not well defined. To address this issue we have modulated BMP activity in a chicken embryo pre-lens ectoderm explant assay, and also studied transgenic mice, in which the type I BMP receptors, Bmpr1a and Acvr1, are deleted from the prospective lens ectoderm. Our results show that chicken embryo pre-lens ectoderm cells express BMPs and require BMP signaling for lens specification in vitro, and that in vivo inhibition of BMP signals in the mouse prospective lens ectoderm interrupts lens placode formation and prevents lens invagination. Furthermore, our results provide evidence that BMP expression is negatively auto-regulated in the lens-forming ectoderm, decreasing when the tissue is exposed to exogenous BMPs and increasing when BMP signaling is prevented. In addition, eyes lacking BMP receptors in the prospective lens placode develop coloboma in the adjacent wild type optic cup. In these eyes, Bmp7 expression increases in the ventral optic cup and the normal dorsal-ventral gradient of BMP signaling in the optic cup is disrupted. Pax2 becomes undetectable and expression of Sfrp2 increases in the ventral optic cup, suggesting that increased BMP signaling alter their expression, resulting in failure to close the optic fissure. In summary, our results suggest that negative and positive auto-regulation of BMP expression is important to regulate early eye development.

Zebrafish mab21l2 mutants possess severe defects in optic cup morphogenesis, lens and cornea development

“…65 In addition, the Xenopus ortholog, xmab21l2, antagonizes overexpression of BMP4, and coimmunoprecipitates with SMAD1, 9 providing some support for a model in which mab21l2 is involved in the regulation of BMP signaling. Disruption of BMP signaling can lead to lens and choroid fissure closure defects, 47,64 like those observed in mab21l2 −/− mutants, suggesting a potential unifying theme underlying each of these ocular defects. Combined with the observation that mab21l2 −/− mutants have smaller lenses, it is possible that the cornea and lens phenotypes are linked by means of abnormal BMP signaling; in this model, more surface ectodermal cells would be specified to a corneal fate over a lens fate, and these cells are also space-limited by concomitant defects in optic cup morphology and size, which together result in the severe anterior segment defects detected in mab21l2 −/− mutants.…”

“…Lens and corneal cells come from a common pool of surface ectodermal precursors, and mab21l2 is expressed in this region in chick and zebrafish . Specification of these cells as lens or cornea is determined in part by BMP signaling, and it is known that manipulations of BMP signaling can affect corneal and lens development . mab‐21, the C. elegans mab21l2 ortholog and founding member of this gene family, has been shown to act antagonistically with members of the TGFβ signaling cascade in regulation of male tail morphology .…”

Signaling and Gene Regulatory Networks in Mammalian Lens Development

“…Active canonical BMP signaling, evaluated by pSmad1/5/8 nuclear stainings, is confined to the dorsal part of the optic cup [54]. In the lens-forming ectoderm, BMP expression is negatively autoregulated [135] and this is independent of Smad1, Smad5, or Smad4 [52]. BMP signals stemming from the lens specify the neuroretina [136], and loss of BMP4 in the optic vesicle is detrimental for lens formation along with the neuroretina being converted into the RPE [54].…”

Systems biology of lens development: A paradigm for disease gene discovery in the eye

“…Fgf, Bmp, etc. ) function in lens development and fiber differentiation (Belecky-Adams et al, 2002; Faber et al, 2001; Furuta and Hogan, 1998; Garcia et al, 2011, 2011, 2005; Huang et al, 2015, 2003; Kuracha et al, 2011; Li et al, 2014; Madakashira et al, 2012; Rajagopal et al, 2008; Simirskii et al, 2007; Sugiyama et al, 2013; Upadhya et al, 2013; Wawersik et al, 1999; Zhang et al, 2016; Zhao et al, 2008). These topics are covered elsewhere (Cvekl and Ashery-Padan, 2014).…”