Mafa-dependent GABAergic activity promotes mouse neonatal apneas
While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa 4A ) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath...
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Veröffentlicht in: | Nature communications 2022-06, Vol.13 (1), p.3284-3284, Article 3284 |
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Sprache: | eng |
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Zusammenfassung: | While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa
4A
) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath holding apneas and death in newborn
Mafa
4A/4A
mutant mice. This apneic breathing is phenocopied by restricting the mutation to central GABAergic inhibitory neurons and by activation of inhibitory Mafa neurons while reversed by inhibiting GABAergic transmission centrally. We find that Mafa activates the
Gad2
promoter in vitro and that this activation is enhanced by the mutation that likely results in increased inhibitory drives onto target neurons. We also find that Mafa inhibitory neurons are absent from respiratory, sensory (primary and secondary) and pontine structures but are present in the vicinity of the hypoglossal motor nucleus including premotor neurons that innervate the geniohyoid muscle, to control upper airway patency. Altogether, our data reveal a role for Mafa phosphorylation in regulation of GABAergic drives and suggest a mechanism whereby reduced premotor drives to upper airway muscles may cause apneic breathing at birth.
Apneas are associated with many pathological conditions. Here, the authors show in a mouse model that stabilization of the transcription factor Mafa in brainstem GABAergic neurons may contribute to apnea, by decreasing motor drive to muscles controlling the airways. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-022-30825-3 |