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      Figure 1. Development of the pituitary gland in mouse   

      Tri-dimensional tissue organization

      The advent of powerful tissue imaging technologies led us to collaborate with colleagues in Montpellier, France towards elucidation of the tri-dimensional organization of the pituitary gland. This work revealed the unexpected organization of pituitary cells into homotypic cell networks in which all cells of the same lineage contact similar cells144, such that these cells exchange signals for the production of coordinated responses. In addition, these homotypic networks interact with each other as they are set up during organ development141.

      Figure 2. Development of pituitary homotypic cell networks

      Mechanisms of cell specification

      Our investigation of transcriptional regulatory mechanisms for expression of pituitary hormone-coding genes led us to discover a number of critical transcription factors such as the Pitx subfamily of homeodomain proteins72, 79, 85, 92, 99, the Tbox factor Tpit96, 103, 104, and more recently, the critical role of Pax7 as selector of intermediate pituitary identity. We are using the full spectrum of genome technologies to identify other regulators of pituitary cell specification139 and in particular, we are investigating the mechanism used by Pax7 to pioneer chromatin remodelling and reshape the epigenome in order to program an alternate cell fate146. Few factors have been shown to have pioneer activity and hence we have a unique system to understand how chromatin is reprogrammed152, 156, 158.

         

      Figure 3. Differentiation of pituitary cells                                           Figure 4. Enhancer opening by the pioneer factor Pax7

      Hormonal regulation of gene expression

      Expression of the POMC gene is tightly regulated by central (brain) mediators or systemic (blood-borne) hormones such as glucocorticoids124. We have defined mechanisms of POMC gene activation by hypothalamic CRH74, 75, 90, 102, 135 as well as negative feedback regulation by glucocorticoids and their receptor GR. Both actions are mediated by transcription factors of the nuclear receptor family, either GR75, 115 or orphan nuclear receptors of the Nur subfamily, Our investigations have led to discovery of new response elements74, 75, of mechanisms involving protein-protein tethering that results in mutual antagonism (trans-repression)61, 75, 145 as well as to identification of key components of glucocorticoid-dependent repression of POMC. Further, we identified disregulation of these mechanisms in pituitary adenomas that cause Cushing disease122, 137, 157. More recently we investigated the role of the Mediator complex in transcriptional regulation.

      Figure 5 POMC gene regulatory sequences

      Cushing’s disease and pituitary adenomas

      In addition to studies of glucocorticoid resistance in pituitary adenomas that cause Cushing disease122, 137, 157, we have also investigated the control of cell cycle in normal pituitary development and in these adenomas. This work led to identification of unique mechanisms for cell cycle exit in pituitary progenitors (stem cells) as opposed to the control of cell cycle134 and tissue maintenance in the adult gland149.

      Specification of hindlimb identity

      Our discovery of the first member of the Pitx family of homeodomain regulators (Pitx1)72 led us to investigate the role of Pitx1, Pitx2 and Pitx3 in development. Each of these factors has varied and striking roles in development and disease. Pitx1 is the master gene for specification for hindlimb identity, i.e. it is the master gene accounting for differences between hindlimbs (legs) and forelimbs (arms, wings)73, 87, 101. We use genome-wide approaches to define the actions of Pitx1, and also the downstream factor Tbx4, in patterning hindlimb development136.

          

      Figures 6 and 7. Specification of hindlimb identity by the transcription factors Pitx1 and Tbx4

      Pitx transcription factors in development

      We also investigated the role of Pitx3 in midbrain dopaminergic neurons. Pitx3 has very restricted expression in the brain and it is a survival factor for those neurons that are the most sensitive to degeneration in Parkinson disease78, 105, 120. Hence, Pitx3 and the gene network that it controls are candidates to explain the particular sensitivity of those neurons to degeneration in Parkinson disease. Recently, we identified a Pitx3-dependent signalling component that is also critical for neuron survival and that, when mutated, leads to late-onset degeneration that is very similar to the human pathology in Parkinson disease153.

      Pitx2 and Pitx3 are both critical regulators of skeletal muscle development, in particular at the transition between precursors and muscle cells. The two Pitx factors play sequential123, 127, 138, and only partly redundant, roles and their loss of function leads to muscle atrophy151.

      Reference numbers refer to complete Publication List 

       

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