HOXA5 plays tissue-specific roles in the developing respiratory system

Abstract

<i>Hoxa5</i> is essential for development of several organs and tissues. In the respiratory system, loss of <i>Hoxa5</i> function causes neonatal death due to respiratory distress. Expression of HOXA5 protein in mesenchyme of the respiratory tract and in phrenic motor neurons of the central nervous system led us to address the individual contribution of these <i>Hoxa5</i> expression domains using a conditional gene targeting approach. <i>Hoxa5</i> does not play a cell-autonomous role in lung epithelium, consistent with lack of HOXA5 expression in this cell layer. In contrast, ablation of <i>Hoxa5</i> in mesenchyme perturbed trachea development, lung epithelial cell differentiation and lung growth. Further, deletion of <i>Hoxa5</i> in motor neurons resulted in abnormal diaphragm innervation and musculature, and lung hypoplasia. It also reproduced the neonatal lethality observed in null mutants, indicating that the defective diaphragm is the main cause of impaired survival at birth. Thus, <i>Hoxa5</i> possesses tissue-specific functions that differentially contribute to the morphogenesis of the respiratory tract.