Development of the brainstem respiratory circuit

Focus Article

Meike E. Heijden, Huda Y. Zoghbi

Published Online: Dec 09 2019

DOI: 10.1002/wdev.366

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Abstract The respiratory circuit is comprised of over a dozen functionally and anatomically segregated brainstem nuclei that work together to control respiratory rhythms. These respiratory rhythms emerge prenatally but only acquire vital importance at birth, which is the first time the respiratory circuit faces the sole responsibility for O2/CO2 homeostasis. Hence, the respiratory circuit has little room for trial‐and‐error‐dependent fine tuning and relies on a detailed genetic blueprint for development. This blueprint is provided by transcription factors that have specific spatiotemporal expression patterns along the rostral‐caudal or dorsal‐ventral axis of the developing brainstem, in proliferating precursor cells and postmitotic neurons. Studying these transcription factors in mice has provided key insights into the functional segregation of respiratory control and the vital importance of specific respiratory nuclei. Many studies converge on just two respiratory nuclei that each have rhythmogenic properties during the prenatal period: the preBötzinger complex (preBötC) and retrotrapezoid nucleus/parafacial nucleus (RTN/pF). Here, we discuss the transcriptional regulation that guides the development of these nuclei. We also summarize evidence showing that normal preBötC development is necessary for neonatal survival, and that neither the preBötC nor the RTN/pF alone is sufficient to sustain normal postnatal respiratory rhythms. Last, we highlight several studies that use intersectional genetics to assess the necessity of transcription factors only in subregions of their expression domain. These studies independently demonstrate that lack of RTN/pF neurons weakens the respiratory circuit, yet these neurons are not necessary for neonatal survival because developmentally related populations can compensate for abnormal RTN/pF function at birth. This article is categorized under: Nervous System Development > Vertebrates: Regional Development

Schematic of the brainstem respiratory circuit. Note: All outlined areas are brainstem nuclei that contribute to respiratory control. Dotted nuclei have intrinsic rhythmogenic properties. Red outline nuclei are either intrinsic chemosensitive properties or are key relay nuclei for chemosensitive signals. Orange nuclei are motor nuclei of cranial nerves that control airflow through the upper airways. Purple nuclei are predominantly active during the inspiratory phase. Green nuclei are predominantly active during the expiratory phase. The role of all other nuclei is described in more depth in Section 2. Abbreviations: BötC, Bötzinger complex; cVRG, caudal ventral respiratory group; ITR, intertrigeminal region; KF, Kölliker Fuse; mV, trigeminal motor nucleus; mVII, facial motor nucleus; mXII, hypoglossal motor nucleus; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; PBN, parabrachial nuclei; PiCo, postinspiratory complex; preBötC, preBötzinger complex; RTN/pF, retrotrapezoid nucleus/parafacial nucleus; rVRG = rostral ventral respiratory group

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Dorsal‐ventral patterning genes in the developing brainstem. Note: Transcription factors indicated with “^†” are essential for neonatal survival. Genes before brackets are expressed in proliferating progenitor cells whereas transcription factors between brackets “()” are expressed in postmitotic neurons. Genes in bold are discussed in the text. Note, not all transcription factors mentioned in this figure are present in all rhombomeres. Specifically, Atoh1* is not expressed in all dB2 neurons but only in a subset of neurons in r2 and r5 domains

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Rhombomeric expression of rostral‐caudal patterning genes. Note: Transcription factors indicated with “^†” are essential for neonatal survival. Abbreviations: vi, fourth ventricle; r1–r7, rhombomere 1–7

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