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Team 2 : Regulations during morphogenesis (Levi)

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During embryonic development Dlx transcription factors are key regulators of morphogenesis ; later in life they play an important role in the control of tissue homeostasis (for example in bone) and of reproduction. Team 2 will tackle these different functional levels with three main objectives :

  1. Provide new insight on the development, function and pathology of the female and male reproductive systems.
  2. Understand how complex craniofacial structures adapted to predation are formed during development ; suggest possible scenarios for their evolution and for the origin of certain craniofacial malformations.
  3. Analyze the role of Dlx genes in mantaining tissue homeostasis and integrity in the adult, particularly in bone and in the nervous system.

We will generate conditional and inducible mutations of Dlx5, Dlx6 and their downstream targets at specific developmental and/or postnatal stages and in specific organs. These same genetic models will be used to trace the destiny of precursor cells in the presence or absence of these transcription factors or to ablate Dlx5/6-positive cells at specific times and locations. These in vivo genetic strategies will be complemented by transcriptome profiling and whole genome approaches to identify and validate the molecular pathways involved in the processes under investigation.

Objective 1 : We have shown that the transcription factors Dlx5 and Foxl2 have opposite effects on the regulation of steroid hormones and on reproduction. Inactivation or allelic reduction of Dlx5/6 results in reduced testosterone levels and infertility. More recently we have collected new data showing that in the female reproductive tract Foxl2 and Dlx5 are also strongly expressed in the uterus where they display a complementary expression pattern. Foxl2 is predominantly expressed by the uterine stroma while Dlx5 is mostly present in the glandular component of the endometrium. Using the genetic models described above we will first address the functional role of Dlx5 and Foxl2 in the development and function of the reproductive system. Then, to identify potential targets of activation/repression of the Dlx5/6-FoxL2→StAR regulatory network in the control of steroidogenesis, whole genome analysis will be carried out to map genomic Dlx5 and Dlx6 binding sites. Genome wide in vivo occupancy will be addressed using ChIP-Seq analysis in extracts from testis, ovary, uterus, Leydig cells and granulosa cells.

Objective 2 : We have previously shown that Dlx5 and Dlx6 are necessary and sufficient to specify maxillo-mandibular identity during embryonic development. We want now to explore how this specification process takes place and which are the evolutionary implications for the origin of gnathostome jaws. We will then focus on the odontogenic role of Dlx5 and Dlx6 and analyse their function in determining the shape, position and identity of teeth and in the control of their differentiation. This project may provide more general cues as to how dynamic changes in epithelial-mesenchymal interactions might have been at the origin of muscularized, functional jaws adapted for predation.

Objective 3 : Dlx5 and Dlx6 participate to determine stem and progenitor cell differentiation in the bone and in the brain. Our new conditional mutant mice will permit to analyze the function of Dlx genes in the adult, dissect their role in maintaining tissue homeostasis and identify factors perturbing their function.

Team leader
Giovanni Levi, DR CNRS

Researchers, professors and assistant professors
Anne Bachelot, PR UPMC
David Costantini, PR MNHN
Nicolas Narboux-Nême, MC MNHN

Anatasia Da Silva-Rocha, TCN CNRS
Gladys Alfama, TCN CNRS

Camille de Lombares, PhD student