Atoh1 Governs the Migration of Postmitotic Neurons that Shape Respiratory Effectiveness at Birth and Chemoresponsiveness in Adulthood

Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
Neuron (Impact Factor: 15.05). 09/2012; 75(5):799-809. DOI: 10.1016/j.neuron.2012.06.027
Source: PubMed


Hindbrain neuronal networks serving respiratory, proprioceptive, and arousal functions share a developmental requirement for the bHLH transcription factor Atoh1. Loss of Atoh1 in mice results in respiratory failure and neonatal lethality; however, the neuronal identity and mechanism by which Atoh1-dependent cells sustain newborn breathing remains unknown. We uncovered that selective loss of Atoh1 from the postmitotic retrotrapezoid nucleus (RTN) neurons results in severely impaired inspiratory rhythm and pronounced neonatal death. Mice that escape neonatal death develop abnormal chemoresponsiveness as adults. Interestingly, the expression of Atoh1 in the RTN neurons is not required for their specification or maintenance, but is important for their proper localization and to establish essential connections with the preBötzinger Complex (preBötC). These results provide insights into the genetic regulation of neonatal breathing and shed light on the labile sites that might contribute to sudden death in newborn infants and altered chemoresponsiveness in adults.

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Article: Atoh1 Governs the Migration of Postmitotic Neurons that Shape Respiratory Effectiveness at Birth and Chemoresponsiveness in Adulthood

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    • "RTN originates from an Egr-2-dependent embryonic domain (rhombomeres 3/5) and co-expresses Atoh-1 and Phox2b during late embryogenesis (Dubreuil et al., 2009; Ramanantsoa et al., 2011). Deletion of any one of these three transcription factors prevents RTN from developing (Ruffault et al., 2015) or, in the case of Atoh-1, from establishing proper connections (Huang et al., 2012). RTN or the RTN region has been described as an inspiratory rhythm generator, an oscillator for active expiration, or a central respiratory chemoreceptor (Guyenet, 2008; Marina et al., 2010; Pagliardini et al., 2011; Wittmeier et al., 2008). "
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    ABSTRACT: Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. During exercise, central command and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 09/2015; 87(5):946-61. DOI:10.1016/j.neuron.2015.08.001 · 15.05 Impact Factor
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    • "The caudal boundary of rhombomere 5 is based on the caudal extent of labeling in EGR2 (early growth factor 2, aka Krox20) transgenic mouse lines (Voiculescu et al., 2001; Manzanares et al., 2002). The rostral boundary of rhombomere 7 is based on the rostral extent of HoxA4 expression while the caudal boundary is an estimate based on size (Rivkin and Cordes, 2008; Huang et al., 2012). Figures 2B–J outlines the regions where distinct developmentally defined cells are located within the neonatal medulla at approximately 100 μm rostro-caudal resolution . "
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    ABSTRACT: The medullary reticular formation contains large populations of inadequately described, excitatory interneurons that have been implicated in multiple homeostatic behaviors including breathing, viserosensory processing, vascular tone, and pain. Many hindbrain nuclei show a highly stereotyped pattern of localization across vertebrates suggesting a strong underlying genetic organization. Whether this is true for neurons within the reticular regions of hindbrain is unknown. Hindbrain neurons are derived from distinct developmental progenitor domains each of which expresses distinct patterns of transcription factors (TFs). These neuronal populations have distinct characteristics such as transmitter identity, migration, and connectivity suggesting developmentally expressed TFs might identify unique subpopulations of neurons within the reticular formation. A fate-mapping strategy using perinatal expression of reporter genes within Atoh1, Dbx1, Lmx1b, and Ptf1a transgenic mice coupled with immunohistochemistry (IHC) and in situ hybridization (ISH) were used to address the developmental organization of a large subset of reticular formation glutamatergic neurons. All hindbrain lineages have relatively large populations that extend the entire length of the hindbrain. Importantly, the location of neurons within each lineage was highly constrained. Lmx1b- and Dbx1- derived populations were both present in partially overlapping stripes within the reticular formation extending from dorsal to ventral brain. Within each lineage, distinct patterns of gene expression and organization were localized to specific hindbrain regions. Rostro-caudally sub-populations differ sequentially corresponding to proposed pseudo-rhombomereic boundaries. Dorsal-ventrally, sub-populations correspond to specific migratory positions. Together these data suggests the reticular formation is organized by a highly stereotyped developmental logic.
    Frontiers in Neuroanatomy 05/2013; 7:7. DOI:10.3389/fnana.2013.00007 · 3.54 Impact Factor
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    ABSTRACT: Breathing is an essential behavior that presents a unique opportunity to understand how the nervous system functions normally, how it balances inherent robustness with a highly regulated lability, how it adapts to both rapidly and slowly changing conditions, and how particular dysfunctions result in disease. We focus on recent advancements related to two essential sites for respiratory rhythmogenesis: (a) the preBötzinger Complex (preBötC) as the site for the generation of inspiratory rhythm and (b) the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) as the site for the generation of active expiration. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see for revised estimates.
    Annual Review of Physiology 10/2012; 75(1). DOI:10.1146/annurev-physiol-040510-130049 · 18.51 Impact Factor
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