Transcription factors regulating the specification of brainstem respiratory neurons

Abstract

Breathing (or respiration) is an unconscious and complex motor behavior which neuronal drive emerges from the brainstem. In simplistic terms, respiratory motor activity comprises two phases, inspiration (uptake of oxygen, O2) and expiration (release of carbon dioxide, CO2). Breathing is not rigid, but instead highly adaptable to external and internal physiological demands of the organism. The neurons that generate, monitor, and adjust breathing patterns locate to two major brainstem structures, the pons and medulla oblongata. Extensive research over the last three decades has begun to identify the developmental origins of most brainstem neurons that control different aspects of breathing. This research has also elucidated the transcriptional control that secures the specification of brainstem respiratory neurons. In this review, we aim to summarize our current knowledge on the transcriptional regulation that operates during the specification of respiratory neurons, and we will highlight the cell lineages that contribute to the central respiratory circuit. Lastly, we will discuss on genetic disturbances altering transcription factor regulation and their impact in hypoventilation disorders in humans.

Molecular organization of autonomic, respiratory, and spinally-projecting neurons in the mouse ventrolateral medulla

“…Reelin, which is expressed in respiratory-related neurons (Tan et al, 2012), was also enriched in n05, n12, along with 7 other clusters. Pax2 , which is expressed by many excitatory, but not inhibitory, respiratory-related neurons (Wu et al, 2017; Xia et al, 2022) was enriched in n12 and n18 supporting the possibility that these clusters contain excitatory respiratory-related neurons. Finally, neurons regulating diaphragm activity are reported to be enriched with Cdh6 and Cdh10, in addition to Cdh9, in embryonic mouse medulla (Vagnozzi et al, 2022).…”

Mechanisms of robustness in gene regulatory networks involved in neural development

“…For example, in the development of the neural tube, a gradient of Sonic Hedgehog (Shh) control cell types along the ventral-dorsal axis. Interestingly, the Shh gradient is able to create boundaries that define cell type in a very robust manner (Hernandez-Miranda et al, 2017 ; Sagner and Briscoe, 2017 , 2019 ; Xia et al, 2022 ). This process uses Shh concentration along time and space as input, and depends on incoherent feedforward (Mangan and Alon, 2003 ) and feedback loops that connect Shh signaling with the expression of the Olig2, Nkx2.2, and Pax6 transcriptional regulators (Balaskas et al, 2012 ).…”

Genetic identification of novel medullary neurons underlying congenital central hypoventilation syndrome

“…29.542652 doi: bioRxiv preprint manifestation of CCHS (12). Unlike PHOX2B that has multiple functions in visceral neurons across the central and peripheral nervous system, the function of LBX1 is limited to specific neuron types in the medulla and spinal cord (29)(30)(31)(32)(33)(34)(35). Interestingly, homozygous Lbx1 FS mutant mice recapitulate the severe respiratory phenotypes observed in CCHS and seem to display a unique deficit in the development of at least two medullary neuron groups that co-express both Lbx1 and Phox2b (12).…”

“…In mice, Lbx1 is essential for the specification of four distinct medullary neuron types known as dB1, dB2, dB3 and dB4 (30,31,(33)(34)(35). Notably, dB2 neurons are the only neuron type in the entire nervous system that co-expresses Lbx1 and Phox2b during development (12,30,31,35,36).…”

“…In mice, Lbx1 is essential for the specification of four distinct medullary neuron types known as dB1, dB2, dB3 and dB4 (30,31,(33)(34)(35). Notably, dB2 neurons are the only neuron type in the entire nervous system that co-expresses Lbx1 and Phox2b during development (12,30,31,35,36). These neurons originate from a discrete pool of Phox2b+ progenitor cells called the dB2 progenitor domain, which transiently resides between rhombomeres 2 and 6 (reviewed in 31,35).…”