Development of the Neuroendocrine Hypothalamus

Abstract

The neuroendocrine hypothalamus consists of neurosecretory neurons and specialized glia of the median eminence and posterior pituitary. Neurons and glia act together to support and regulate reciprocal brain–body communications that enable the hypothalamus to anticipate and adapt to changing physiological conditions. Here we summarize recent studies in model organisms that show how an embryonic program of hypothalamic development unfolds in a manner that underlies adult function. Fate-mapping studies in chick show that much of the basal hypothalamus is built from a multipotent Fgf10(+) progenitor population whose mode of growth in four dimensions suggests a new model for hypothalamic development that we term the ‘Anisotropic growth’ model. Conditional genetic analyses and pharmacological interventions in mouse, zebrafish, and chick suggest that a conserved molecular mechanism may mediate anisotropic growth and establish the basal hypothalamus. A handful of conserved signalling factors and transcription factors (TFs) direct the progressive development of Fgf10(+) progenitors to hypothalamic progenitors, hypothalamic neurons, and then infundibular progenitors of the median eminence and posterior pituitary in a program where space and time are intrinsically linked. These studies reveal additionally that Fgf10(+) cell populations are maintained throughout life and are vital to the long-term building, maintenance, and function of the adult hypothalamo–pituitary axis. We speculate on whether the embryonic Fgf10(+) progenitor population harbours a hypothalamic stem cell and discuss the implications for the ability of the hypothalamus to adapt to changing physiological conditions on different time scales through life.

Key References

• Alvarez-Bolado et al. (2012)—Lineage-tracing of a subset of Shh(+) neuroepithelial progenitors shows that they contribute to the tuberal and mammillary hypothalamus.

• Carreno et al. (2017)—Genetic studies in the mouse reveal the integrated development of the ventral hypothalamus (including the infundibulum and Shh(+) neuroepithelial progenitors) and the adenohypophysis.

• Chen et al. (2017)—A large scale single cell RNA seq analysis of the adult mouse hypothalamus confirms that neuroendocrine neurohormones/neurotransmitters are expressed in heterogeneous cell types.

• Corman et al. (2018)—Sophisticated mouse studies, including analyses of conditional knock-out and reporter lines, show that tuberal neurons derive from both Shh-expressing and Shh-responsive progenitors.

• Fu et al. (2017)—Fate-mapping and pharmacological studies in the early chick provides evidence for the anisotropic growth model of hypothalamic development.

• Haan et al. (2013)—Evidence for de novo adult neurogenesis from Fgf10(+) tanycytes; together with Fu et al. (2017) and Robins et al. (2013), raises possibility that an Fgf10(+) population is important for building hypothalamic neurons throughout life.

• Kim et al. (2019)—A new study that sets a benchmark for molecular analysis of the developing hypothalamus. Single cell RNA seq analyses of the hypothalamus at different time points in embryogenesis and postnatal life provide evidence for the early specification of key hypothalamic neuronal subsets. Comparison of wild type and mutant mice provides evidence that the hypothalamus is a diencephalic-derived structure.

• Manning et al. (2006)—A study in the chick embryo that provided an understanding of the co-ordination of pattern and proliferation of ventral hypothalamic progenitor cells. Re-interpretation of this paper, in light of the anisotropic growth shown in Fu et al. (2019), suggests that the cells that express Tbx2/BMP are bHyp cells, and the Emx2+ cells are mammillary progenitors.

• Muthu et al. (2016)—Anisotropic growth of anterior hypothalamus in zebrafish; absence of growth leads to failure of differentiation of both ‘anterior’ and ‘tuberal’ neuroendocrine neurons.

• Newman et al. (2018a)—Sophisticated conditional knock-out and reporter lines show hypothalamus is of diencephalic origin.

• Orquera et al. (2016)—Evidence for conserved mechanism of anterior progenitor growth and differentiation, via a Shh-Rax pathway.

• Robins et al. (2013)—Analysis of adult mouse shows that Fgf10(+) stem/progenitor cells exist as tanycytes that line the ventricle; with Fu et al. (2019) and Haan et al. (2013), suggests that Fgf10(+) stem/progenitor cells are retained through life.

• Shimogori et al. (2010)—A large-scale screen and in situ analysis identifies many hypothalamic progenitor domains; conditional knock-out of subsets of Shh(+) neuroepithelial progenitors shows importance in anterior/tuberal growth and neurogenesis.

• Szabó et al. (2009)—Lineage-tracing of a subset of Shh(+) RDVM cells shows contribution to tuberal and mammillary hypothalamus.

• Tessmar-Raible et al. (2007)—Conservation of neuroendocrine cells and conservation of key molecules.

• Trowe et al. (2013)—Analysis of mouse, analysing control of Shh expression in RSVM cells. With Manning et al. (2006), suggests a mechanism for resolution of bHyp cells into Shh(+) and Shh(−) domains.

• Xu et al. (2007)—Proof-of-principle that differentiating hypothalamic neurons undergo tangential migration.

• Zhao et al. (2008)—Proof-of-principle that progenitors other than bHyp cells also undergo tangential migration.