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Development of the Neuroendocrine Hypothalamus

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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. © 2016 American Physiological Society. Compr Physiol 6:623‐643, 2016.

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Figure 1. Figure 1. Architecture of the hypothalamus. (A) Position of the hypothalamus relative to rest of the brain; box marks the magnified view shown in B. (B) Hypothalamus is divided into preoptic area, anterior, tuberal, and posterior hypothalamus from left to right. Positions of hypothalamic nuclei, areas and components of neurohypophysis are shown. Neurohypophysis is defined by median eminence, pituitary stalk and posterior lobe of the pituitary. Abbreviations: Och, optic chiasm; PH, preoptic hypothalamus; SCN, suprachiasmatic nucleus; AH, anterior hypothalamic area; PVN, paraventricular nucleus; APV, anterior periventricular nucleus; Aba, anterobasal nucleus; VMN, ventromedial nucleus; DMN, dorsomedial nucleus; LH, lateral hypothalamic area; Arc, arcuate nucleus; ME, median eminence; TMN, tuberomammillary nucleus; PM, premammillary hypothalamus; TMT, tuber mammillary terminal; M, mammillary hypothalamus; SM, supramammillary hypothalamus; MB, mammillary bodies, ME, median eminence; Post. Lobe, posterior lobe.
Figure 2. Figure 2. Arrangement of nuclei and neuronal differentiation. Left‐hand panel shows arrangement of nuclei around the third ventricle of the adult tuberal/anterodorsal hypothalamus, and shows tanycytes (yellow cells) bordering the third ventricle. Right‐hand panel shows how known transcription factors direct anterodorsal hypothalamic and tuberal progenitors into immature and then mature PVN, APV, SON, DMN, VMN, and Arc neurons. See () for additional details.
Figure 3. Figure 3. Schematized fate maps of forebrain. Top panels show schematized fate maps of forebrain regions, including hypothalamus. Disputes over models of forebrain development [e.g. ()] center around whether the hypothalamus and telencephalon are a single unit [secondary prosencephalon ()], or whether the hypothalamus is part of the diencephalon (). Bottom panels show spatial relationship between axial mesoderm and overlying neural tissue. Dynamic relative tissue movements mean that hypothalamic progenitors are exposed to a range of axial mesoderm‐derived signals.
Figure 4. Figure 4. Signaling factors in hypothalamic induction and regionalization. (A) In the early neural tube, Wnt antagonists promote anterior neural/ prosencephalic fate by repressing Wnt signaling. Shh signaling from prechordal mesoderm induces Shh expression in RDVM cells/hypothalamic floor plate. Note, where Shh terminates patterns of gene expression that are induced secondarily are in an arc‐like pattern, rather than bilaterally symmetrical. (B) Later, BMP signaling in the prechordal mesoderm downregulates Shh in the hypothalamic floor. Shh is induced in the adjacent basal plate and the hypothalamic floor plate upregulates Fgf and BMP. Wnt antagonism determines hypothalamic versus posterior floor plate identity. (C) The prechordal mesoderm moves relatively caudally and tuberal regions are now underlain, instead, by Rathke's pouch. Fgf expression becomes restricted rostrally and BMP caudally, further defining the tuberomammillary region. Wnt signaling restricts the size of these domains. Rax (rx3 in zebrafish) is expressed in the anterior/tuberal region and emx2 in posterior mammillary region. Abbreviations: PM, prechordal mesoderm; Hyp.BP, hypothalamic basal plate; Hyp.FP, hypothalamic floor plate; RP, Rathke's pouch.
Figure 5. Figure 5. Axial mesoderm signals pattern RDVM cells. (A) Fate mapping studies show that at HH stage 6 RDVM cells lie transiently over NC cells expressing Shh. (B) RDVM cells then move rostrally and are in register with the prechordal mesoderm, the source of Nodal and BMP signals. Hatched diagonal lines indicate prospective hypothalamus.
Figure 6. Figure 6. Combinatorial gene expression patterns define hypothalamic territories. (A) The developing hypothalamus is dorsoventrally divided into alar plate, anterobasal plate/basal plate and floor plate. (B) Schematic summarizes early gene expression patterns that begin to regionalize the hypothalamus. (C) Schematic summarizes late gene expression patterns that will further define regions within the hypothalamus as separate nuclei form (shown in D). (D) Schematic shows general position of nascent hypothalamic nuclei and areas.
Figure 7. Figure 7. Hypothalamic‐neurohypophyseal interfaces. Posterior lobe of the pituitary and median eminence receive axonal projections from hypothalamic nuclei. Magnocellular neurons project to the posterior lobe (blue) and parvocellular neurons project to the median eminence (green). As well as the neuronal terminals, blood capillaries (red) are found in close proximity to glial cells (light blue): tanycytes in the median eminence and pituicytes in the posterior lobe. Abbreviations: AVP, vasopressin; OXT, oxytocin; CRH, corticotrophin‐releasing hormone; TRH, thyrotrophin‐releasing hormone; GHRH, growth hormone‐releasing hormone; DA, dopamine.


Figure 1. Architecture of the hypothalamus. (A) Position of the hypothalamus relative to rest of the brain; box marks the magnified view shown in B. (B) Hypothalamus is divided into preoptic area, anterior, tuberal, and posterior hypothalamus from left to right. Positions of hypothalamic nuclei, areas and components of neurohypophysis are shown. Neurohypophysis is defined by median eminence, pituitary stalk and posterior lobe of the pituitary. Abbreviations: Och, optic chiasm; PH, preoptic hypothalamus; SCN, suprachiasmatic nucleus; AH, anterior hypothalamic area; PVN, paraventricular nucleus; APV, anterior periventricular nucleus; Aba, anterobasal nucleus; VMN, ventromedial nucleus; DMN, dorsomedial nucleus; LH, lateral hypothalamic area; Arc, arcuate nucleus; ME, median eminence; TMN, tuberomammillary nucleus; PM, premammillary hypothalamus; TMT, tuber mammillary terminal; M, mammillary hypothalamus; SM, supramammillary hypothalamus; MB, mammillary bodies, ME, median eminence; Post. Lobe, posterior lobe.


Figure 2. Arrangement of nuclei and neuronal differentiation. Left‐hand panel shows arrangement of nuclei around the third ventricle of the adult tuberal/anterodorsal hypothalamus, and shows tanycytes (yellow cells) bordering the third ventricle. Right‐hand panel shows how known transcription factors direct anterodorsal hypothalamic and tuberal progenitors into immature and then mature PVN, APV, SON, DMN, VMN, and Arc neurons. See () for additional details.


Figure 3. Schematized fate maps of forebrain. Top panels show schematized fate maps of forebrain regions, including hypothalamus. Disputes over models of forebrain development [e.g. ()] center around whether the hypothalamus and telencephalon are a single unit [secondary prosencephalon ()], or whether the hypothalamus is part of the diencephalon (). Bottom panels show spatial relationship between axial mesoderm and overlying neural tissue. Dynamic relative tissue movements mean that hypothalamic progenitors are exposed to a range of axial mesoderm‐derived signals.


Figure 4. Signaling factors in hypothalamic induction and regionalization. (A) In the early neural tube, Wnt antagonists promote anterior neural/ prosencephalic fate by repressing Wnt signaling. Shh signaling from prechordal mesoderm induces Shh expression in RDVM cells/hypothalamic floor plate. Note, where Shh terminates patterns of gene expression that are induced secondarily are in an arc‐like pattern, rather than bilaterally symmetrical. (B) Later, BMP signaling in the prechordal mesoderm downregulates Shh in the hypothalamic floor. Shh is induced in the adjacent basal plate and the hypothalamic floor plate upregulates Fgf and BMP. Wnt antagonism determines hypothalamic versus posterior floor plate identity. (C) The prechordal mesoderm moves relatively caudally and tuberal regions are now underlain, instead, by Rathke's pouch. Fgf expression becomes restricted rostrally and BMP caudally, further defining the tuberomammillary region. Wnt signaling restricts the size of these domains. Rax (rx3 in zebrafish) is expressed in the anterior/tuberal region and emx2 in posterior mammillary region. Abbreviations: PM, prechordal mesoderm; Hyp.BP, hypothalamic basal plate; Hyp.FP, hypothalamic floor plate; RP, Rathke's pouch.


Figure 5. Axial mesoderm signals pattern RDVM cells. (A) Fate mapping studies show that at HH stage 6 RDVM cells lie transiently over NC cells expressing Shh. (B) RDVM cells then move rostrally and are in register with the prechordal mesoderm, the source of Nodal and BMP signals. Hatched diagonal lines indicate prospective hypothalamus.


Figure 6. Combinatorial gene expression patterns define hypothalamic territories. (A) The developing hypothalamus is dorsoventrally divided into alar plate, anterobasal plate/basal plate and floor plate. (B) Schematic summarizes early gene expression patterns that begin to regionalize the hypothalamus. (C) Schematic summarizes late gene expression patterns that will further define regions within the hypothalamus as separate nuclei form (shown in D). (D) Schematic shows general position of nascent hypothalamic nuclei and areas.


Figure 7. Hypothalamic‐neurohypophyseal interfaces. Posterior lobe of the pituitary and median eminence receive axonal projections from hypothalamic nuclei. Magnocellular neurons project to the posterior lobe (blue) and parvocellular neurons project to the median eminence (green). As well as the neuronal terminals, blood capillaries (red) are found in close proximity to glial cells (light blue): tanycytes in the median eminence and pituicytes in the posterior lobe. Abbreviations: AVP, vasopressin; OXT, oxytocin; CRH, corticotrophin‐releasing hormone; TRH, thyrotrophin‐releasing hormone; GHRH, growth hormone‐releasing hormone; DA, dopamine.
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How to Cite

Sarah Burbridge, Iain Stewart, Marysia Placzek. Development of the Neuroendocrine Hypothalamus. Compr Physiol 2016, 6: 623-643. doi: 10.1002/cphy.c150023