TEMPORAL CONTROL OF EPIDERMAL GENE NETWORKS: A MULTISCALE INTEGRATIVE APPROACH – ChronoNet

A key problem of developmental biology is to understand what causes cells in a part of an embryo to regularly adopt a behavior, while neighboring cells concurrently adopt another. Good progresses have been made to understand how spatial patterns of gene expression are setup, and define which subsets of cells undergo a differentiation program. Embryos yet develop in a four dimensional space and little is known on the mechanisms underlying the temporal control of developmental sequences, and how cells integrate time signals for their differentiation.

Developmental timing involves genetically encoded mechanisms, as exemplified by the vertebrate segmentation clock. A systemic control is yet to consider for synchronizing among tissues, within an organism, patterns of gene expression and behaviors to execute key developmental transitions, for example puberty in humans or metamorphosis in many animal species. Modifications in developmental timing have a wide range of implications, from birth defects to evolution. Determining how the intrinsic (genetic) and extrinsic (systemic) timing programs are regulated at the molecular level is thus of fundamental importance in deciphering how an organism develops in interaction with its environment.

We aim to address this question through analyzing the molecular mechanisms that underlie the developmental timing of epidermis differentiation in flies. Previous work has established epidermal trichomes as a fruitful paradigm of morphological differentiation and evolution, within one of the best-understood framework of development. We now have a wealth of knowledge concerning the genetically hard-wired mechanisms of this Gene Regulatory Network that determine the spatial patterning of embryonic trichome cells, and then activate intimate cellular effectors to ultimately execute trichome differentiation. The whole program of epidermal differentiation needs yet to be reactivated at regular intervals, to achieve post-embryonic developmental transitions throughout the drosophila life-cycle. They are two molting cycles, when the epidermal cuticle is shed and resynthesized to accommodate increased body size, and metamorphosis, a stunning remodeling in which adult tissues are made and differentiate. Both larval and pupal transitions are orchestrated by pulses of a steroid hormone, ecdysone. Recent work demonstrates that ecdysone production provides a systemic control, integrating inputs from the internal and external milieu, including tissue growth and body size, nutritional intake and light. Therefore, elucidation of the temporal control of epidermal trichomes offers the opportunity to connect genetic and systemic components of developmental timing.

Our goal is to provide a comprehensive understanding and modeling of the molecular mechanisms that repeatedly time execution of the trichome program throughout the life cycle, and define the consequences of their developmental and environmental modifications.
Our strategy is based on an integrative multiscale approach, gathering a multidisciplinary consortium of complementary expertise. It incorporates state to the art molecular genetics, functional genomics, physiology, quantitative live imaging, statistical physics, informatics and mathematical modeling. Achievements of each member and preliminary results support the feasibility of this proposal and its potential to provide significant advances to our general understanding of developmental timing.

Our specific objectives are to:
1) Identify the genome-wide set of regulatory interactions that time epidermal differentiation and how they are synchronized with whole body development,
2) Unravel reciprocal coordination between tissue morphogenesis and cell differentiation,
3) Decipher and model how timing cues implement distinct patterns of expression.