Hillier, R. | Search bioRxiv

bioRxiv2024

ZFHX3 plays a role in pain and cautious-like behaviours in mice

A missense mutation in zinc finger homeobox-3 (ZFHX3) gene is known to alter circadian rhythms and metabolism. ZFHX3 is highly expressed in the central nucleus of amygdala and so we investigated whether female and male Zfhx3Sci-/+ mice have impaired pain, fear, anxiety-like, and cautious-like behaviours as these behaviours which are associated with the central nucleus of the amygdala. Using mechanical and thermal sensitivity test, the fear conditioning test and the light-dark box test, we found that female Zfhx3Sci-/+ mice have hypoalgesia to mechanical stimulus while hyperalgesia to heat stimulus. Additionally, both female and male Zfhx3Sci-/+ display reduction of cautious-like behaviour. While neither female and male Zfhx3Sci-/+ mice showed a difference in fear conditioning or anxiety-like behaviour, we have demonstrated for the first time that ZFHX3 is involved in pain and cautious behaviours. HighlightsO_LIFemale and male Zfhx3Sci/+ mice displayed less cautious-like behaviour C_LIO_LIZfhx3Sci/+ female mice had hypoalgesia to noxious mechanical stimulus C_LIO_LIZfhx3Sci/+ female mice had hyperalgesia to noxious heat stimulus C_LI

animal behavior and cognition↗

bioRxiv2022

A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice.

A protein altering variant in the gene encoding zinc finger homeobox-3 (ZFHX3) has recently been associated with lower BMI in a human genome-wide association study. We investigated metabolic parameters in mice harbouring a missense mutation in Zfhx3 (Zfhx3Sci/+) and looked for altered in situ expression of transcripts that are associated with energy balance in the hypothalamus to understand how ZFHX3 may influence growth and metabolic effects. One year old male and female Zfhx3Sci/+ mice weighed less, had shorter body length, reduced fat mass, smaller mesenteric fat depots, and lower circulating insulin, leptin, and insulin-like growth factor-1 (IGF1) concentrations than Zfhx3+/+ littermates. In a second cohort of 9 - 20-week-old males and females, Zfhx3Sci/+ mice ate less than wildtype controls, in proportion to body weight. In a third cohort of female-only Zfhx3Sci/+ and Zfhx3+/+ mice that underwent metabolic phenotyping from 6 - 14 weeks old, Zfhx3Sci/+ mice weighed less and had lower lean mass and energy expenditure, but fat mass didnt differ. We detected increased expression of somatostatin, and decreased expression of growth hormone-releasing hormone and growth hormone-receptor mRNAs in the arcuate nucleus (ARC). Similarly, ARC expression of orexigenic neuropeptide Y was decreased and ventricular ependymal expression of orphan G protein-coupled receptor Gpr50 was decreased. We demonstrate for the first time an energy balance effect of the Zfhx3Sci mutation, likely by altering expression of key ARC neuropeptides to alter growth, food intake and energy expenditure.

physiology↗