Cranial placodes are thickenings of the embryonic head ectoderm that give rise to cells of the sensory organs (the optic lens, the olfactory epithelium and the inner ear), the adenohypophysis, and a subset of cranial ganglia. Defects in cranial placodes development cause a wide array of human congenital diseases ranging from blindness, deafness and anosmia, to hormone imbalance and orofacial sensory deficits. Therefore, defining the molecular mechanisms regulating the emergence of cranial placode progenitor is critical to understand these conditions. While they produce very diverse cell types such as sensory neurons, lens fibers and hormone secreting cells, all placode progenitors arise from a common precursor field that borders the anterior neural plate known as the pre-placodal region (PPR). The PPR eventually segregates into distinct domains in which cells will adopt fate characteristic for each sensory placode. We have previously shown that the transcription factor Zic1 is necessary and sufficient to promote cranial placodes fate. In a microarray screen designed to identify genes activated by Zic1 during placode specification in Xenopus embryos, we recovered several factors involved in retinoic acid (RA) metabolism and function, including lipocalin type prostaglandin D2 synthase (LPGDS), a retinoic acid carrier, retinaldehyde dehydrogenase 2 (RALDH2), the enzyme responsible for the synthesis of retinoic acid from its precursor retinal, a retinoic acid metabolizing enzyme, Cyp26c, and the cellular retinoic acid binding protein 2 (CRABP2), signifying the importance of retinoic acid signaling in placode formation downstream of Zic1. The proposed experiments are crafted to test the hypothesis that Zic1 controls placode progenitor formation non-cell autonomously by regulating retinoic acid production, transport and degradation at the anterior neural plate. We have designed three specific aims to specifically address this question. (1) We will delineate the molecular mechanisms by which Zic1 establishes the PPR in a non-cell autonomous manner though the activation of LPGDS, RALDH2 and Cyp26c. (2) We will analyze the fate of the placode progenitors generated in response to Zic1 in an explant assay, and identify the factors that cooperate with RA signaling to generate the full spectrum of placode derivatives. (3) We will characterize the nuclear receptors mediating Zic1-activated RA signaling during cranial placode progenitor formation. The proposed experiments will establish the role of RA in the regulation of placode fate, and more broadly define the importance of RA signaling in craniofacial development.
Cranial placodes are thickenings of the embryonic head ectoderm that contribute to the specialized paired sense organs and to the sensory cranial ganglia. In this application we propose to characterize the factors that regulate the formation of cranial placode progenitors, focusing more specifically on the role of a metabolite of vitamin A, retinoic acid. Defining the molecular mechanisms regulating placode progenitor formation is critical to understand a wide array of human congenital malformations ranging from anosmia, blindness and deafness to orofacial sensory deficits.
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