Impairing retinoic acid signalling in the neural crest cells is sufficient to alter entire eye morphogenesis

Abstract

Retinoic acid (RA) is known to be required at various levels of eye patterning via Retinoic Acid Receptors (RAR); however the molecular and cellular mechanisms triggered by these nuclear receptors are still obscure. The genetic studies performed here enable us to present a new model to study RA action during eye development. By inactivating the three RARs, specifically in the periocular mesenchyme, we discriminate the individual contribution of each RAR during eye development and describe a new function for RARs during the formation of the optic nerve. We demonstrate that RARalpha is the only receptor that mediates RA signalling in the neurectoderm during ocular development. Surprisingly, and despite a sophisticated pattern of RA-activity in the developing retina, we observed that RA signalling is not autonomously required in this tissue for eye formation. We show that the action of RA during eye morphogenesis is occurring specifically in neural crest-derived periocular mesenchyme and is mediated by all three RARs. Furthermore, we point out that Pitx2, which encodes a homeodomain transcription factor, is a key RA-responsive gene in neural crest cells during eye development. Interestingly, we observed that RA is required in the neural crest cells for normal position of the extraocular muscle.

Retinoic acid receptors exhibit cell‐autonomous functions in cranial neural crest cells

“…This is accounted for by the functional redundancy between Rarb and Rarg in the periocular mesenchyme (Matt et al, 2005(Matt et al, , 2008, rather than in the bone anlagen (present study). Thus, our data show that RARa and RARc are the functional receptors transducing the RA signal in frontonasal NCC.…”

“…First, conventional germline RAR compound null mutants display a broad spectrum of abnormalities affecting a variety of organs constituted by cells of multiple origins. Second, RARs exhibit widespread and rapidly changing expression patterns in the developing embryo (Dollé, 2009), and RA is a secreted molecule which can act in a paracrine manner (Matt et al, 2005(Matt et al, , 2008Duester, 2008;Niederreither and Dollé, 2008). To overcome these difficulties and to gain insights into the functions of RA, it was necessary to produce and analyze mice in which RARs were specifically ablated in NCC.…”

“…The additional ablation of Rarb (yielding Rara/b/g NCCÀ/À mutants) does not increase the severity or penetrance of the craniofacial skeletal defects, but induces severe ocular malformations (Matt et al, 2008 for a full description). This is accounted for by the functional redundancy between Rarb and Rarg in the periocular mesenchyme (Matt et al, 2005(Matt et al, , 2008, rather than in the bone anlagen (present study).…”

“…Of interest, a similar situation has been observed in the developing ocular region: RA is synthesized by the retinal pigmented epithelium, the retina and the corneal ectoderm [all derived from the (neuro)ectoderm], and it orchestrates eye morphogenesis through diffusing to the NCC-derived periocular mesenchyme where it activates RXR/RAR heterodimers. Surprisingly, during these two processes RARs would have no autonomous function in the ectodermal tissues (Matt et al, 2005(Matt et al, , 2008.…”

Corneal endothelium: developmental strategies for regeneration

“…16 TGFb1 and TGFb2 have been shown to increase the expression of Foxc1 and Pitx2, 17,18 which are required for the development of the ocular anterior segment. [19][20][21] It has been proposed that the TGF-b subfamily members initiate a supporting mechanism to regulate Pax6 function and transcription. 22 In the corneal endothelium, TGFb1 and TGFb2 modulate cell proliferation, cell morphology, and collagen expression.…”