Institut de recherches cliniques de Montréal
P 514 987-5680
Development, differentiation, transcription, pituitary function and hormone actionWe use the investigation of transcriptional regulatory mechanisms as a starting point to discover regulators of development, cell differentiation and hormone action. Thus, we discovered Pitx1, the prototype of a family of three homeodomain transcription factors that play a critical role in early development. In addition to their joint roles in pituitary and craniofacial organogenesis, Pitx1 and Pitx2 each mark one half of the lateral plate mesoderm (the posterior half for Pitx1 and the left for Pitx2) in agreement with the role of Pitx1 as master gene for specification of hindlimb identity and with the role of Pitx2 as effector for left-right lateralization during formation of internal organs such as the heart, lungs and stomach. We are particularly interested in the role of these factors in pituitary function and of Pitx1 in the specification of hindlimb identity. Also, Pitx2 and Pitx3 are sequentially expressed during muscle formation and we study their respective roles in myogenesis. We also study the role of Pitx factors in cell proliferation and for Pitx3, its role in midbrain dopaminergic neuron survival and putative involvement of Pitx3-dependent functions in Parkinson’s disease.We have thus found that the transcription factor Pax7 specifies intermediate lobe identity through a pioneer factor activity. Pioneer factors have the unique ability to access their DNA target sites in compacted (closed) chromatin and initiate chromatin remodelling (opening). We use the breath of genetic and genomic technologies to understand the still poorly defined mechanism of pioneering.We also discovered a T-box factor called Tpit that is a positive regulator for cell-fate determination of corticotrope and melanotrope cells of the pituitary, as well as a negative regulator of gonadotrope differentiation. In addition to cell-fate mechanisms, we also study the pituitary gene expression program using genomic methodologies such as ChIPseq and expression profiling by RNAseq. These whole genome approaches have already yielded new cell-specific pituitary regulators and identified candidate co-regulators involved in hormone action.Our transcriptional studies have primarily used the pituitary pro-opiomelanocortin (POMC) gene as a model. Transcription of this gene is activated by the hypothalamic hormone CRH and repressed by glucocorticoids and their receptor (GR). The action of CRH is mediated through orphan nuclear receptors related to NGFIB (Nur77), Nurr1 and Nor1. We study the mechanism of action of these nuclear receptors as well as the trans-repression exerted by GR on their activity.While the discovery of Tpit led us to identify a previously unrecognized form of ACTH deficiency that is lethal for children bearing TPIT mutations, the identification of proteins critical for trans-repression led us to define mechanisms of glucocorticoid resistance that is the hallmark of corticotrope adenomas causing Cushing’s disease.
- Roussel-Gervais A, Couture C, Langlais D, Takayasu S, Balsalobre A, Rueda BR, et al. The Cables1 gene in glucocorticoid regulation of pituitary corticotrope growth and Cushing disease. J Clin Endocrinol Metab. 2015; 101(2):513-522.
- Mayran A, Pelletier A, Drouin J. Pax factors in transcription and epigenetic remodelling. Semin Cell Dev Biol. 2015; 44:135-144.
- Bifsha P, Yang J, Fisher RA, Drouin J. Rgs6 is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra. PLoS Genet. 2014;10(12):e1004863.
- L’honore A, Commere PH, Ouimette JF, Montarras D, Drouin J, Buckingham M. Redox regulation by Pitx2 and Pitx3 is critical for fetal myogenesis. Dev Cell. 2014;29(4):392-405.
- Langlais D, Couture C, Drouin J. The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome. Molecular Cell. 2012;47(1):38-49.
- Budry L, Balsalobre A, Gauthier Y, Khetchoumian K, L’honore A, Vallette S, et al. The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling. Genes Dev. 2012;26(20):2299-310.
- Langlais D, Couture C, Kmita M, Drouin J. Adult pituitary cell maintenance: lineage-specific contribution of self-duplication. Mol Endocrinol. 2013;27(7):1103-12.
- Mollard P, Hodson DJ, Lafont C, Rizzoti K, Drouin J. A tridimensional view of pituitary development and function. Trends Endocrinol Metab. 2012;23(6):261-9.
- Ouimette JF, Lavertu Jolin M, L’Honoré A, Gifuni A, Drouin J. Divergent transcriptional activities determine limb identity. Nature Communications. 2010;1(4):1-9.