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Ontogenetic rules for the molecular diversification of hypothalamic neurons

Nature Reviews Neuroscience volume 23, pages 611–627 (2022)Cite this article

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Abstract

The hypothalamus is an evolutionarily conserved endocrine interface that, among other roles, links central homeostatic control to adaptive bodily responses by releasing hormones and neuropeptides from its many neuronal subtypes. In its preoptic, anterior, tuberal and mammillary subdivisions, a kaleidoscope of magnocellular and parvocellular neuroendocrine command neurons, local-circuit neurons, and neurons that project to extrahypothalamic areas are intermingled in partially overlapping patches of nuclei. Molecular fingerprinting has produced data of unprecedented mass and depth to distinguish and even to predict the synaptic and endocrine competences, connectivity and stimulus selectivity of many neuronal modalities. These new insights support eminent studies from the past century but challenge others on the molecular rules that shape the developmental segregation of hypothalamic neuronal subtypes and their use of morphogenic cues for terminal differentiation. Here, we integrate single-cell RNA sequencing studies with those of mouse genetics and endocrinology to describe key stages of hypothalamus development, including local neurogenesis, the direct terminal differentiation of glutamatergic neurons, transition cascades for GABAergic and GABAergic cell-derived dopamine cells, waves of local neuronal migration, and sequential enrichment in neuropeptides and hormones. We particularly emphasize how transcription factors determine neuronal identity and, consequently, circuit architecture, and whether their deviations triggered by environmental factors and hormones provoke neuroendocrine illnesses.

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Fig. 1: Regionalization of the hypothalamus and its transcription factor determinants.
Fig. 2: Models of hypothalamic neurogenesis and the role of gene regulatory networks in neuronal specification.
Fig. 3: The leptin-dependent formation of axonal projections.

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Acknowledgements

The authors thank E.O. Tretiakov for conceptual discussions on data analysis and interpretation. This work was supported by the Swedish Research Council (2020-01688 to T.Hö., 2018-02838 to T.Ha.); Novo Nordisk Foundation (NNF20OC0063667 to T.Ha., T.Hö.); Hjärnfonden (FO2019-0277 to T.Ha.), European Research Council (SECRET-CELLS, 2015-AdG-695136 and FOODFORLIFE, 2020-AdG-101021016 to T.Ha.) and intramural funds of the Medical University of Vienna (T.Ha.).

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Authors and Affiliations

  1. Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Marco Benevento & Tibor Harkany

  2. Department of Neuroscience, Biomedicum 7D, Karolinska Institutet, Solna, Sweden

    Tomas Hökfelt & Tibor Harkany

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  1. Marco Benevento
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  2. Tomas Hökfelt
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  3. Tibor Harkany
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All authors contributed to researching data for the article, substantial discussion of content and writing the article. M.B. and T.Ha. reviewed and edited the manuscript before submission.

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Correspondence to Tibor Harkany.

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Glossary

Infundibulum

Tubular structure that connects the posterior pituitary to the hypothalamus.

Autonomic behaviours

Unconscious behavioural responses that are evoked by reflex arcs.

Fast neurotransmitter

A chemical messenger loaded into synaptic vesicles by high-affinity vesicular transporters and released by excitable cells at specialized junctions to induce electrochemical signals through voltage-gated receptors to activate or inhibit target cells.

Neuropeptide

A small protein that is released extrasynaptically from large dense core vesicles and that binds to metabotropic G protein-coupled receptors, activating second messenger cascades to regulate gene transcription, modulate synaptic transmission and/or stabilize circuit connectivity.

Transcription factor

A protein that modulates gene transcription by directly binding to specific DNA sequences at the gene promoter.

Convergence

An inward flux from multiple points of origin to an infinitesimal volumetrically defined space. In molecular neurobiology, convergence is used for transcription factors to jointly identify cell types.

Divergence

An outward flux from a single point of origin to a volumetrically defined space around the initial point. In molecular neurobiology, divergence describes when cell fate is shaped by differential gene expression within gene regulatory networks driven by an identical master gene.

Telencephalic

Relating to the telencephalon, the anterior subdivision of the encephalic vesicle that generates the neocortical structures in vertebrates.

Neuromere

A morphologically and molecularly defined transient segment or subdivision of the developing nervous system.

Diencephalic

Relating to the diencephalon, the encephalic subdivision between the telencephalon and the brainstem, chiefly corresponding to thalamic areas.

Gene regulatory networks

(GRNs). Also known as regulons; a matrix of interacting genes arranged around a master gene and regulated in a hierarchical fashion as a single unit. A GRN thus includes differentially expressed genes reflecting cell states.

Mesoderm

An embryonic germinal layer positioned between the ectoderm and the endoderm that consists of progenitor cells that generate bone, cartilage, musculature and the vascular system.

Ectoderm

The most external embryonal germinal layer populated by progenitor cells that generate the skin and the nervous system (neuroectoderm).

Conjoined invagination

An inward fold of two adjacent anatomical structures.

Radial glia scaffold

A basic map of processes emanating from radial glial cells that serves as a guidance structure for migrating neuroblasts.

Neural progenitor cells

(NPCs). A fate stage that precedes that of the neural precursors and in which multi-potency is retained.

Cell-autonomous stochastic fate restriction

A set of randomized genetic commands in a given cell that determines the cell’s molecular identity, independent from any external influence.

Genetic cascade

A hierarchical temporal succession of upstream gene expression commands that activate or repress downstream genetic programmes to drive cell-fate specification.

Microdomains

Circumscribed regions in the brain that exhibit a specific molecular signature.

Nucleokinesis

The active translocation of the nucleus during cell migration.

Tanycytes

A type of radial glia positioned along the mid-ventral wall of the third ventricle in the adult brain.

Neural precursor cells

A tissue-specific cell type that retains some reproductive potential but can give rise to only a limited number of cell lineages intrinsic to the particular tissue in which it resides.

Epigenetic regulatory mechanisms

Molecular commands that regulate gene expression and protein translation without altering the DNA sequence through post-translational modifications of histones, mRNA and microRNAs, amongst others.

Adhesion molecules

Cell-surface proteins that establish and stabilize physical contacts between cells or with the extracellular matrix.

Pro-opiomelanocortin

(POMC). A multifunctional neuropeptide precursor that gives rise to α-melanocyte-stimulating hormone, adrenocorticotropic hormone and β-endorphin upon enzymatic cleavage.

Gene selectors

Genes encoding transcription factors that are necessary to specify or differentiate anatomical areas.

Minipuberty

Physiological activation of the hypothalamic–pituitary–gonadal axis that occurs in early postnatal stages and is necessary for gonadal development and fertility.

Chromatin condensation

The process of compacting long stretches of DNA around histone octamers that prevents transcription factor binding, leading to gene silencing.

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Benevento, M., Hökfelt, T. & Harkany, T. Ontogenetic rules for the molecular diversification of hypothalamic neurons. Nat Rev Neurosci 23, 611–627 (2022). https://doi.org/10.1038/s41583-022-00615-3

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