Etchevers:Notebook/STRA6 in eye development

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Project Description/Abstract

  • STRA6 was our entry point into working on a number of other neural crest-expressed genes that are critical for eye morphogenesis, mostly transcription factors. More about that later. This is Nicolas' developing Ph.D. project and Adeline's M2R (masters' degree) as well, in between when they are practicing medical genetics.
  • As of 2008, the project looks like this (in French).
  • Les micro/anophtalmies, absence ou réduction du globe oculaire, sont les plus sévères des malformations de l’œil. Leur incidence est estimée à environ 1sur 5000 naissances. Plusieurs gènes ont été récemment impliqués dans ces anomalies du développement oculaire. Il s’agit en large majorité de facteurs de transcription exprimés précocement dans le développement oculaire (PAX6, SOX2, OTX2, RAX, et à un moindre degré CHX10). Ces gènes sont fortement conservés au cours de l’évolution et jouent un rôle dans le développement des yeux et de la tête même chez les invertébrés.
  • Des mutations de SOX2 sont impliquées dans 10 à 20 % des micro/anophtalmies, alors que les autres gènes ne sont impliqués que dans un très faible pourcentage. Nous avons récemment recherché des mutations de ces gènes chez 80 patients atteints de micro/anophtalmies, et avons pu identifier l’anomalie génétique causale chez seulement 30 % d’entre eux.
  • Face à l’hétérogénéité déjà mise en évidence, d’autres gènes de micro/anophtalmies restent à identifier. Notre hypothèse est qu’il pourrait s’agir de gènes exprimés précocement dans le développement oculaire et régulés par les facteurs de transcription déjà impliqués dans les micro/anophtalmies. Des relations étroites entre ces protéines ont été démontrées lors de la morphogenèse oculaire chez les animaux modèles. Il existe ainsi des boucles de régulation d’expression génique impliquant ces facteurs de transcription dans un réseau transcriptionnel dont les détails restent largement à définir.
  • Nous souhaitons donc étudier les réseaux transcriptionnels à un stade précoce du développement oculaire humain (vers six semaines de développement). Nous définirons des gènes régulés par chacun des 4 principaux facteurs de transcription impliqués chez l’homme dans les micro/anophtalmies (PAX6, SOX2, RAX et OTX2) par la méthode d’immunoprécipitation chromatinienne (ChIP), qui permet de recueillir les fragments d’ADN où sont liés physiquement ces facteurs de transcription. Ces fragments d’ADN seront secondairement analysés par clonage et séquencage classique, ou par séquençage haut débit, permettant, pour chacun des 4 facteurs de transcription étudiés, d’obtenir une base de données des gènes régulés dans l’ébauche oculaire embryonnaire humaine.

Notes

  • Cliquer sur une date pour modifier l'entrée pour ce jour-la.
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