A novel genetic mouse model of osteoporosis with double heterozygosity of Irx3 and Irx5 characterizes sex-dependent phenotypes in bone homeostasis.

Iroquois homeobox gene 3 (Irx3) and Irx5 encode transcription factors that play crucial roles in limb development and bone formation. Previous studies using knockout mice have revealed a role of Irx3 and Irx5 in osteogenesis in young adult mice. However, whether these genes are also essential for bone homeostasis in adulthood and contribute to bone diseases remain poorly understood.

Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity.

Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2 tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries.

Deficiency of Irx5 protects mice from obesity and associated metabolic abnormalities.

Objective: Obesity, a leading cause of several metabolic abnormalities, is mainly caused by imbalanced energy homeostasis. IRX3 and IRX5 have been suggested as genetic determinants of obesity in connection with the intronic variants of the FTO gene, the strongest genetic risk factor of polygenic obesity in humans. Although the causal effects of Irx3 and its cooperation with Irx5 in obesity and associated metabolic abnormalities have been demonstrated in vivo, the function of Irx5 in energy homeostasis remains unclear.

and - Novel Regulatory Factors of Postnatal Hypothalamic Neurogenesis.

The hypothalamus is a brain region that exhibits highly conserved anatomy across vertebrate species and functions as a central regulatory hub for many physiological processes such as energy homeostasis and circadian rhythm. Neurons in the arcuate nucleus of the hypothalamus are largely responsible for sensing of peripheral signals such as leptin and insulin, and are critical for the regulation of food intake and energy expenditure. While these neurons are mainly born during embryogenesis, accumulating evidence have demonstrated that neurogenesis also occurs in postnatal-adult mouse hypothalamus, particularly in the first two postnatal weeks.

Ectopic expression of and in the paraventricular nucleus of the hypothalamus contributes to defects in haploinsufficiency.

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of -expressing neurons critical for feeding regulation. haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects of haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations of PVH neurons, which are differentially affected by haploinsufficiency.

Irx3 and Irx5 in Ins2-Cre cells regulate hypothalamic postnatal neurogenesis and leptin response.

Obesity is mainly due to excessive food intake. IRX3 and IRX5 have been suggested as determinants of obesity in connection with the intronic variants of FTO, but how these genes contribute to obesity via changes in food intake remains unclear. Here, we show that mice doubly heterozygous for Irx3 and Irx5 mutations exhibit lower food intake with enhanced hypothalamic leptin response.