Respiratory consequences of targeted losses of gene function in mice.

Fetal development of the respiratory tract and diaphragm requires strict coordination between genetically controlled signals and mechanical forces produced by the neural network that generates breathing. HOXA5, which is expressed in the mesenchyme of the trachea, lung and diaphragm, and in phrenic motor neurons, is a key transcription factor regulating lung development and function. Consequently, most mutants die at birth from respiratory failure. However, the extensive effect of the null mutation makes it difficult to identify the origins of respiratory dysfunction in newborns. To address the physiological impact of tissue-specific roles, we used conditional gene targeting with the and mouse lines to produce specific deletions in the mesenchyme and motor neurons, respectively. expression in the mesenchyme is critical for trachea development, whereas its expression in phrenic motor neurons is essential for diaphragm formation. Breathing measurements in adult mice with whole-body plethysmography demonstrated that, at rest, only the motor neuron deletion affects respiration, resulting in higher breathing frequency and decreased tidal volume. But subsequent exposure to a moderate hypoxic challenge (i =0.12; 10 min) revealed that both mutant mice hyperventilate more than controls. ; mice showed augmented tidal volume while ; mice had the largest increase in breathing frequency. No significant differences were observed between medulla-spinal cord preparations from E18.5 control and ; mouse embryos that could support a role for in fetal inspiratory motor command. According to our data, expression in the mesenchyme and phrenic motor neurons controls distinct aspects of respiratory development.