Development of the brainstem respiratory circuit

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

Early Steps towards Hearing: Placodes and Sensory Development

“…For a neuronal progenitor cell to exit the cell cycle and proceed to differentiate, the initial upregulation of Gmnn , Foxd4 , Zic s and Sox genes must be downregulated [ 37 , 38 , 42 , 43 ]. Following the downregulation of the various proliferative genes, bHLH genes involved in neuronal differentiation in the CNS become expressed in dorso-ventral expression patterns within the developing neural tube to regulate fates of neurons within various subdomains [ 44 , 45 ].…”

“…Determination of dorso-ventral identity within the brainstem is governed by the expression of various homeodomain and bHLH transcription factors in restricted areas along the dorso-ventral axis [ 45 , 55 ]. The dorsal brainstem is subdivided into eight domains of neuronal progenitor populations [ 55 ].…”

“…As expected from the expression pattern, loss of Atoh1 eliminates most cochlear nuclei neurons [ 58 ]. Additional genes are expressed in the Olig3 domain including Neurog1/2 (dA2), Ascl1 (dA3-dB1) and Ptf1a (dA4-dB1) [ 45 , 59 ]. For example, the dorsal-most subdomain (dA1), that also expresses Atoh1 , expresses Pax3 , the next subdomain (dA2) expresses Pax3 and Pax7 and the third subdomain (dA3) expresses Pax3 , Pax6 and Pax7 [ 55 ].…”

“…Genes, such as Pou4f1 , are expressed in multiple subdomains (dA1-dA3, dB3) [ 55 ]. Interestingly, Atoh1 , which defines the dorsal-most progenitor population (dA1), is also expressed in a more ventral subpopulation (dB2) during their maturation [ 45 , 55 , 60 ]. Phox2b is expressed in rhombomere 2–6 of the hindbrain (dB2), but not in rhombomere 7 or the spinal cord [ 55 ].…”

mRNA isoform balance in neuronal development and disease

“…During neurodevelopment, these cells assemble into highly organized structures with specific functions in the brain and spinal cord. For example, the establishment of the mammalian respiratory circuit requires the coordinated assembly of premotor neuron populations in the brainstem to generate inspiratory rhythms and motor neuron populations in the spinal cord to exert motor control of the diaphragm (van der Heijden & Zoghbi, 2020; Vagnozzi et al, 2020). Recent advancements in neuroanatomical mapping have identified >150 regions of the human cortex distinguished by function, connectivity, and/or topography (Glasser et al, 2016; A. Irimia et al, 2012).…”