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AMPK phosphorylates LMX1b to regulate a brainstem neurogenic network important for control of breathing in neonatal mice

ABSTRACT: Ventilatory drive is modulated by a variety of neurochemical inputs that converge on spatially oriented clusters of cells within the brainstem. This regulation is required to maintain energy homeostasis and is essential to sustain life across all mammalian organisms. However, the mechanistic understanding of the regulation of these ventilatory control cellular clusters is poorly defined. This study explores the role of AMP-activated protein kinase (AMPK) and LIM homeobox transcription factor 1-beta (Lmx1b), a key player in dorsal-ventral patterning during fetal development, in the regulation of brainstem ventilatory control centers

ORGANISM(S): Mus musculus

PROVIDER: GSE284418 | GEO | 2025/01/15

REPOSITORIES: GEO

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Project description:LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies; however, in the absence of in vivo molecular characterization of their regulation, their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. A tetracycline-inducible expression system and microarray analysis showed that a subset of NF-kappa B target genes, including IL-6 and IL-8 are upregulated in LMX1B-expressing HeLa cells. Chromatin immunoprecipitation assays revealed that LMX1B binds to the proximal promoter region of IL-6 and IL-8 in vivo, in the vicinity of the characterized kappa B site, and that LMX1B recruitment correlates with an increased NF-kappa B DNA association. Inhibition of NF-kappa B activity by short interfering RNA-mediated knock-down of p65 impairs LMX1B-dependent induction of NF-kappa B target genes, while activation of NF-kappa B activity by TNF-alpha results in a synergistic induction of these genes by LMX1B. IL-6 promoter-driven reporter assays showed that the kappa B site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of a number of NF-kappa B target genes is affected in the kidney of Lmx1b-/- knock-out mice, thus supporting the biological relevance of the data obtained in the human cell line. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-kappa B target genes in cooperation with nuclear p50/p65 NF-kappa B. Human subset (GSM303547-GSM303550): Two biological replicates of non-expressing HtTA-LMX1B cells (grown in doxycycline-containing medium) and of LMX1B-expressing HtTA-LMX1B cells (grown for 4 days in doxycycline-free medium) were processed for gene expression array analyses using an Affymetrix platform. Mouse subset (GSM304379-GSM304384): Three kidney samples from newborn wild-type mice and from newborn Lmx1b-/- knock-out mice were processed for gene expression array analyses using an Agilent platform.

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AMPK phosphorylates LMX1b to regulate a brainstem neurogenic network important for control of breathing in neonatal mice

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