Abstract
The precise pattern of motor neuron (MN) activation is essential for the execution of motor actions; however, the molecular mechanisms that give rise to specific patterns of MN activity are largely unknown. Phrenic MNs integrate multiple inputs to mediate inspiratory activity during breathing and are constrained to fire in a pattern that drives efficient diaphragm contraction. We show that Hox5 transcription factors shape phrenic MN output by connecting phrenic MNs to inhibitory premotor neurons. Hox5 genes establish phrenic MN organization and dendritic topography through the regulation of phrenic-specific cell adhesion programs. In the absence of Hox5 genes, phrenic MN firing becomes asynchronous and erratic due to loss of phrenic MN inhibition. Strikingly, mice lacking Hox5 genes in MNs exhibit abnormal respiratory behavior throughout their lifetime. Our findings support a model where MN-intrinsic transcriptional programs shape the pattern of motor output by orchestrating distinct aspects of MN connectivity.
Highlights
Breathing is a fundamental motor behavior required for life
We previously showed that two Hox5 paralogs, Hoxa5 and Hoxc5 are required for the early development and survival of phrenic motor neuron (MN) and the innervation of the diaphragm (Landry-Truchon et al, 2017; Philippidou et al, 2012)
While the neonatal lethality of Hox5MND mice underscores the critical requirement for Hox5 genes in respiration, it had prevented us from examining the role of Hox5 proteins in respiratory behaviors and functional connectivity at postnatal stages
Summary
Breathing is a fundamental motor behavior required for life. In mammals, specialized circuits have evolved to support robust and efficient breathing to cope with changing metabolic demands. The establishment of phrenic motor neuron (MN) identity relies on the intersection of transcription factor-based programs acting along the dorsoventral and rostrocaudal axes of the spinal cord during development (Chaimowicz et al, 2019; Edmond et al, 2017; Philippidou et al, 2012) It is not known whether these MN-intrinsic transcriptional programs are required for the generation of patterned respiratory motor output. Vagnozzi et al showed that removing the Hox transcription factors from motor neurons in the PMC changed their activity and disordered their connections with other breathing-related nerve cells. MNspecific deletion of Hox genes results in a selective loss of inhibitory inputs to PMC neurons and a dramatic change in the activation pattern of phrenic MNs. Our results demonstrate that Hox transcription factors determine phrenic MN topography and connectivity to generate robust breathing behaviors
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