Development of the Neuroendocrine Hypothalamus

Abstract

The neuroendocrine hypothalamus is composed of the tuberal and anterodorsal hypothalamus, together with the median eminence/neurohypophysis. It centrally governs wide-ranging physiological processes, including homeostasis of energy balance, circadian rhythms and stress responses, as well as growth and reproductive behaviours. Homeostasis is maintained by integrating sensory inputs and effecting responses via autonomic, endocrine and behavioural outputs, over diverse time-scales and throughout the lifecourse of an individual. Here, we summarize studies that begin to reveal how different territories and cell types within the neuroendocrine hypothalamus are assembled in an integrated manner to enable function, thus supporting the organism's ability to survive and thrive. We discuss how signaling pathways and transcription factors dictate the appearance and regionalization of the hypothalamic primordium, the maintenance of progenitor cells, and their specification and differentiation into neurons. We comment on recent studies that harness such programmes for the directed differentiation of human ES/iPS cells. We summarize how developmental plasticity is maintained even into adulthood and how integration between the hypothalamus and peripheral body is established in the median eminence and neurohypophysis. Analysis of model organisms, including mouse, chick and zebrafish, provides a picture of how complex, yet elegantly coordinated, developmental programmes build glial and neuronal cells around the third ventricle of the brain. Such conserved processes enable the hypothalamus to mediate its function as a central integrating and response-control mediator for the homeostatic processes that are critical to life. Early indications suggest that deregulation of these events may underlie multifaceted pathological conditions and dysfunctional physiology in humans, such as obesity.

Development of the hypothalamus: conservation, modification and innovation

“…1B), each of which has a lateral, medial and periventricular zone (Markakis, 2002). Each hypothalamic region has distinct patches of nuclei and associated functions (Burbridge et al, 2016). The preoptic area is known to control thermoregulation, reproduction and electrolyte balance.…”

“…For example, a series of Dlx family transcription factors labels GABAergic precursors in the hypothalamus, just as in the basal telencephalon (Petryniak et al, 2007;Yee et al, 2009). Other transcription factors define and/or induce cells that express specific hypothalamic neuropeptides (Bedont et al, 2015;Burbridge et al, 2016), which have now been characterized at the single-cell level (Campbell et al, 2017;Romanov et al, 2016) (Fig. 3, Table 1).…”

“…Located at the most ventral position in the forebrain (Fig. 1A), the hypothalamus has integral developmental and functional connections with the pituitary gland, through which it controls endocrine hormone release (Burbridge et al, 2016). Some of the basic body functions regulated by pituitary hormones and their targets in the adrenal glands, thyroid and gonads include fluid balance, stress response, reproduction and growth.…”

“…Here, we provide an overview of the factors that control the early induction and patterning of the hypothalamus, as well as those that regulate neurogenesis in the embryonic and adult hypothalamus, topics that have been recently reviewed in detail (Bedont et al, 2015;Burbridge et al, 2016). Based on data from multiple model systems, we also speculate that changes in Wnt signaling may modify hypothalamic regionalization and alter the specification and differentiation of neural progenitors in the embryo and adult, and thereby give rise to species-specific hypothalamic circuitry.…”

Development of the basal hypothalamus through anisotropic growth

“…Other experiments begin to reveal that Fgf10 is itself required for growth of the infundibulum: if Fgf10 is reduced, eliminated or dysregulated, the infundibulum does not develop and infundibular cells/infundibular‐derived cells are apoptotic and hypoplastic . Knockout studies in the mouse and analysis of human variants reveal a number of TFs, such as Hes1/Hes5 , that are required for infundibular formation, including Nkx2.1 , Tbx3 and Sox2 . Many of these are likely to affect early steps in the development of bHyp progenitors but conditional knockout studies are beginning to show TFs that act downstream of Fgf signalling and underlie the progression or maintenance of glial infundibular progenitors.…”