Abstract
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. This second wave of active neurogenesis contributes to the remodeling of hypothalamic neuronal populations and regulation of energy homeostasis including hypothalamic leptin sensing. Radial glia cell types, such as tanycytes, are known to act as neuronal progenitors in the postnatal mouse hypothalamus. Our recent study unveiled a previously unreported radial glia-like neural stem cell (RGL-NSC) population that actively contributes to neurogenesis in the postnatal mouse hypothalamus. We also identified Irx3 and Irx5, which encode Iroquois homeodomain-containing transcription factors, as genetic determinants regulating the neurogenic property of these RGL-NSCs. These findings are significant as IRX3 and IRX5 have been implicated in FTO-associated obesity in humans, illustrating the importance of postnatal hypothalamic neurogenesis in energy homeostasis and obesity. In this review, we summarize current knowledge regarding postnatal-adult hypothalamic neurogenesis and highlight recent findings on the radial glia-like cells that contribute to the remodeling of postnatal mouse hypothalamus. We will discuss characteristics of the RGL-NSCs and potential actions of Irx3 and Irx5 in the regulation of neural stem cells in the postnatal-adult mouse brain. Understanding the behavior and regulation of neural stem cells in the postnatal-adult hypothalamus will provide novel mechanistic insights in the control of hypothalamic remodeling and energy homeostasis.
Highlights
Obesity is a global health threat with increased risk for various chronic conditions including diabetes and cardiovascular diseases (Williams et al, 2015; Gonzalez-Muniesa et al, 2017)
Before discussing the potential functions of Irx3 and Irx5 in radial glia-like neural stem cell (RGL-NSC), we provide below a brief review of postnatal-adult neurogenesis and description of different radial glia-like cells (RGLs) cell types residing in the hypothalamus
IRX3 and IRX5 have emerged as a strong link between the noncoding genetic variations of the Fat mass and obesity-associated gene (FTO) gene and obesity
Summary
Obesity is a global health threat with increased risk for various chronic conditions including diabetes and cardiovascular diseases (Williams et al, 2015; Gonzalez-Muniesa et al, 2017). Irx and Irx are expressed in multiple cell types of the ARC-ME, predominantly in a newly identified radial glia-like neural stem cell (RGLNSC) population in the postnatal mouse hypothalamus (Smemo et al, 2014; Campbell et al, 2017; Son et al, 2021a). They are implicated in the regulation of energy homeostasis, feeding regulation, and postnatal hypothalamic neurogenesis (Son et al, 2021a). We aim to provide an update integrating our knowledge of their new functions in hypothalamic neurogenesis and discuss the intricacies and challenges in understanding their molecular actions
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