Étude du rôle tissu-spécifique des gènes Hoxa5 et Yy1 dans le développement du système respiratoire de la souris
|Abstract:||Hox genes encode transcription factors governing complex developmental processes including the anteroposterior patterning of the embryo axis, the specification of the axial and appendicular skeletons as well as the formation of the nervous system and several organs. In the respiratory system, the role of Hoxa5 is critical since the loss of Hoxa5 function causes death at birth of a high proportion of mutant pups due to respiratory distress. HOXA5 protein expression in the mesenchyme of the respiratory tract and in the phrenic motor neurons of the central nervous system led us to address the specific contribution of Hoxa5 in each component to lung development. Using a conditional gene targeting approach, we demonstrated that the genetic ablation of Hoxa5 function in the mesenchyme established the importance of Hoxa5 in trachea development, lung epithelial cell differentiation and lung growth. In parallel, the specific deletion of Hoxa5 in motor neurons resulted in abnormal innervation of the diaphragm, altered diaphragm musculature and lung hypoplasia which are responsible for the neonatal lethality observed in null mutants. Thus, this confirms that a defective diaphragm mainly contributes to impair survival at birth. Hoxa5 expression is under the control of many regulatory elements, one of which is responsible for Hoxa5 expression in the respiratory and digestive tracts. Yin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. We have shown that YY1 regulates Hoxa5 expression in the lung by binding to the lung-specific regulating sequence. However, the mesenchymal loss of Yy1 function causes a lung phenotype similar to the one observed in Hoxa5-/- mutants including neonatal mortality. We then studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 epithelial mutation resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching and caused airway dilation similar to that seen in human congenital cystic lung diseases, such as the pleuropulmonary blastoma (PPB). Together, our data demonstrate the crucial requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB.|
|Document Type:||Mémoire de maîtrise|
|Open Access Date:||23 April 2018|
|Collection:||Thèses et mémoires|
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