Math1 Is Essential for the Development of Hindbrain Neurons Critical for Perinatal Breathing

Abstract

SUMMARY Mice lacking the proneural transcription factor Math1 (Atoh1) lack multiple neurons of the proprioceptive and arousal systems and die shortly after birth from an apparent inability to initiate respiration. We sought to determine whether Math1 was necessary for the development of hindbrain nuclei involved in respiratory rhythm generation, such as the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), defects in which are associated with Congenital Central Hypoventilation Syndrome (CCHS). Using a new Math1-GFP fusion allele, we traced the development of Math1-expressing pFRG/RTN and paratrigeminal neurons and found that loss of Math1 did indeed disrupt their migration and differentiation. We also identified new Math1-dependent neurons and their projections in the pre-Bötzinger complex, a structure critical for respiratory rhythmogenesis, and found that glutamatergic modulation reestablished a rhythm in the absence of Math1. This study identifies Math1-dependent neurons that are critical for perinatal breathing that may link proprioception and arousal with respiration.

Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1

“…Moreover, induction at E10.5 labeled cells near multiple medullary nuclei associated with respiration: the rostroventrolateral reticular nucleus (RVL), pre-Bötzinger complex (preBötC), and rostral ventral respiratory group (rVRG) (Fig. 2B, levels 4, 5b, 6b), recently described in further detail (23). Table 1 lists all new and known Math1 hindbrain populations.…”

“…Lhx2 and Barhl2, also Math1-dependent (6, 26), appeared similar to Lhx9 [Movies S1-S48 (AVI)]. [These lineages did not coexpress Phox2b, distinguishing them from recently identified neurons with intraparenchymal Math1 expression (23).] Complete sets of serial sections labeled for each transcription factor in both WT and Math1-null hindbrains are available online [Movies S1-S48 (AVI)].…”

Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

“…Many of the activities of the proneural factors were delineated by loss-offunction studies in mice and through genome-wide profiling of their transcription targets [48, 49•]. Studies on mouse mutants have shown that homozygous Atoh1 (Atoh1 -/-) and Ascl1 (Ascl1 -/-)-deficient mice both die in the early postnatal period with feeding and respiratory defects [50,51]. Similarly, homozygous Tcf4 knockout (Tcf4 -/-) mice die within 24 h of birth [20,52].…”

Characterization of the Key Mouse Cochlear Developmental Genes for Auditory Hair Cell Regeneration

“…The Atoh1-EGFP+ is a transgenic line in which only a portion of Atoh1 promoter region, is used to drive EGFP. The recently characterized knock-in Atoh1-EGFP mice 141 might be required to solidify the endogenous Atoh1 expression pattern in the future. This result also supports that heterogeneous ectopic Atoh1 levels were detected in different Atoh1-HA+ cells.…”

“…39,40 To screen for such a drug in a high-throughput manner, mouse embryonic fibroblast cells (MEFs) isolated from Arf is a knock-in mouse model in which the EGFP coding sequence is tagged at the 3' end of Atoh1 gene. 141 MEFs will be treated with different small molecules and turning on EGFP will indicate activation of Atoh1. Thus, EGFP will be used as read-out to judge what small molecules should be used in secondary assays in inner ear cells.…”