Understanding how the master transcriptional regulator HOXA5 defines cell fate in the developing embryo

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Proper control of cell-type specific transcriptional programs is critical for normal development. Mutation of a single transcriptional regulator often produces pleiotropic phenotypes with organ-specific consequences. Therefore, it is fundamental to understand how a single transcription factor confers to cells and tissues their identity by controlling specific transcriptional programs. HOX proteins are evolutionary conserved transcription factors that play critical roles in embryogenesis, organogenesis and tissue homeostasis during postnatal life. Their mutations lead to multiple and various developmental defects and diseases. Despite their broad expression in numerous cell types, HOX proteins perform their regulatory functions in a context-dependent fashion. They bind to similar TNAT motif-rich DNA-binding sites, but confer different regulatory actions in vivo, raising the fundamental question of how specificity of HOX transcriptional outputs is attained. While the developmental role of Hox genes is established, understanding how they act still awaits the identification of target genes. Thus, HOX proteins represent ideal candidates to determine how individual transcription factors govern cell fate. Our long-term objective is to define how HOX transcription factors regulate target gene expression in a highly context-dependent manner during mammalian development. We use HOXA5 as a model, because the loss of Hoxa5 gene function in mice results in a plethora of well-characterized phenotypes and, most importantly, in death at birth due to the combination of respiratory system malformations. These defects include trachea occlusion resulting from cartilage anomalies, lung dysmorphogenesis due to reduced branching, hypoplasia and abnormal cell differentiation, and altered diaphragm innervation and musculature. These phenotypes evoke severe human diseases such as tracheal stenosis, lung hypoplasia and diaphragm eventration. No other single Hox mutants present such an overt respiratory system phenotype revealing the functional predominance of Hoxa5 in this developmental process. Hoxa5 pleiotropic action in the respiratory system suggests cell-specific mechanisms, and makes Hoxa5 an ideal model for studying how individual HOX proteins achieve cell-specificity to orchestrate organ system development. We hypothesize that HOXA5 transcription factor exerts part of its functions through activation of common transcriptional programs but also via the regulation of distinct, context-specific effectors. Our objectives are to define the molecular mechanisms involved in HOXA5 action during the formation of the respiratory system in order to elucidate how HOXA5 attains functional cell-specificity. Our aims are to: 1.Identify and compare the gene networks controlled by the HOXA5 master regulator in the developing trachea, lung and diaphragm 2.Determine the genetic and cellular mechanisms of HOXA5 function in the specific context of trachea formation