Loss of cell adhesion molecule CHL1 improves homeostatic adaptation and survival in hypoxic stress

Abstract

Close homologue of L1 (CHL1) is a transmembrane cell adhesion molecule that is critical for brain development and for the maintenance of neural circuits in adults. Recent studies revealed that CHL1 has diverse roles and is involved in the regulation of recovery after spinal cord injury. CHL1 expression was downregulated in the cerebral cortex, hypothalamus, and brain stem after the induction of acute hypoxia (AH). In the current study, we sought to address the role of CHL1 in regulating homeostasis responses to hypoxia using CHL1-knockout (CHL1−/−) mice. We found that, compared with wild-type littermates, CHL1−/− mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to AH. Immunofluorescence staining revealed that CHL1 was expressed in the carotid body (CB), the key oxygen sensor in rodents, and CHL1 expression level in the CB as assayed by western blot was decreased after hypoxic exposure. The number of glomus cells and the expression of tyrosine hydroxylase (a marker for glomus cells) in the CB of CHL1−/− mice appeared to be increased compared with CHL1+/+ mice. In addition, in the ex vivo CB preparation, hypoxia induced a significantly greater afferent nerve discharge in CHL1−/− mice compared with CHL1+/+ mice. Furthermore, the arterial blood pressure and plasma catecholamine levels of CHL1−/− mice were also significantly higher than those of CHL1+/+ mice. Our findings first demonstrate that CHL1 is a novel intrinsic factor that is involved in CB function and in the ventilatory response to AH.

Methylome repatterning in a mouse model of Maternal PKU Syndrome

“…In the Diet Restricted Group, the Chl1 gene, a likely a target of mir680, was down-regulated (− 3.2 fold). Chl1 was of particular interest as it is down-regulated as a survival mechanism in response to hypoxic-stress [57]. It is possible that stress associated with in utero hyperphenylalaninemia may also down-regulate Chl1.…”

Close Homolog of L1 Deficiency Exacerbated Intestinal Epithelial Barrier Function in Mouse Model of Dextran Sulfate Sodium-Induced Colitis

“…Glial scar expression of CHL1 limits recovery after spinal cord injury CHL1 is a glial scar component that restricts posttraumatic axonal growth and remodeling of spinal circuits by homophilic binding mechanisms. Our previous study had found that CHL1 −/− mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to high altitude hypoxia (Huang et al, 2013). The results indicated that CHL1 plays multitudinous roles in a variety of pathological models.…”

Physiology and Transcriptomics Analysis Reveal the Contribution of Lungs on High-Altitude Hypoxia Adaptation in Tibetan Sheep

“…It is notable that APOLD1 was also one of the most significantly downregulated genes at L altitude compared to those at M altitude, and Hb concentration was lower at both L and H altitudes than at M altitude. CHL1 is associated with homeostatic adaptation during hypoxia, compared with wild-type littermates; CHL1 knockout mice exhibit an augmented ventilatory response after acute hypoxia ( Huang et al, 2013 ); augmented ventilatory responses were also observed in Tibetan sheep ( Wang et al, 2019 ) and Tibetans ( Bigham and Lee, 2014 ) at high altitude. The significantly lower Hb concentration at H altitude weakens the oxygen-carrying capacity of the organism, but the enhanced ventilatory response can compensate to some extent; it is possible that the low expression of CHL1 at H altitude is responsible for the enhanced ventilatory response.…”