Talk:Endocrine - Hypothalamus Development

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Cite this page: Hill, M.A. (2021, June 22) Embryology Endocrine - Hypothalamus Development. Retrieved from


Schredelseker T & Driever W. (2020). Conserved Genoarchitecture of the Basal Hypothalamus in Zebrafish Embryos. Front Neuroanat , 14, 3. PMID: 32116574 DOI. Conserved Genoarchitecture of the Basal Hypothalamus in Zebrafish Embryos

"Analyses of genoarchitecture recently stimulated substantial revisions of anatomical models for the developing hypothalamus‎ in mammalian and other vertebrate systems. The prosomeric model proposes the hypothalamus to be derived from the secondary prosencephalon, and to consist of alar and basal regions. The basal hypothalamus can further be subdivided into tuberal and mamillary regions, each with distinct subregions. Albeit being a widely used model system for neurodevelopmental studies, no detailed genoarchitectural maps exist for the zebrafish (Danio rerio) hypothalamus‎. Here, we compare expression domains of zebrafish genes, including arxa, Shha, otpa, isl1, lhx5, nkx2.1, nkx2.2a, pax6, and dlx5a, the orthologs of which delimit specific subregions within the murine basal hypothalamus. We develop the highly conserved brain-specific homeobox (bsx) gene as a novel marker for genoarchitectural analysis of hypothalamic regions. Our comparison of gene expression patterns reveals that the genoarchitecture of the basal hypothalamus in zebrafish embryos 48 hours post fertilization is highly similar to mouse embryos at E13.5. We found the tuberal hypothalamus in zebrafish embryos to be relatively large and to comprise previously ill-defined regions around the posterior hypothalamic recess. The mamillary hypothalamus is smaller and concentrates to rather medial areas in proximity to the anterior end of the neural tube floor plate. Within the basal hypothalamus we identified longitudinal and transverse tuberal and mamillary subregions topologically equivalent to those previously described in other vertebrates. However, the hypothalamic diencephalic boundary region and the posterior tuberculum still provide a challenge. We applied the updated prosomeric model to the developing zebrafish hypothalamus to facilitate cross-species comparisons. Accordingly, we applied the mammalian nomenclature of hypothalamic organization to zebrafish and propose it to replace some controversial previous nomenclature."


Expression of progesterone receptor, estrogen receptors α and β, and kisspeptin in the hypothalamus during perinatal development of gonad-lacking steroidogenic factor-1 knockout mice

Brain Res. 2019 Jun 1;1712:167-179. doi: 10.1016/j.brainres.2019.02.016. Epub 2019 Feb 15.

Ikeda Y1, Kato-Inui T2, Tagami A3, Maekawa M3.

Gonadal hormones contribute to brain sexual differentiation. We analyzed expression of progesterone receptor (PR), estrogen receptor-α (ERα), ERβ, and kisspeptin, in the preoptic area (POA) and/or the arcuate nucleus (ARC), in gonad-lacking steroidogenic factor-1 knockout (KO) mice during perinatal development. At postnatal-day (P) 0-P7, POA PR levels were higher in wild-type (WT) males compared with WT females, while those in KO males were lower than in WT males and similar to those in WT and KO females. At P14-P21, PR levels in all groups increased similarly. POA ERα levels were similar in all groups at embryonic-day (E) 15.5-P14. Those in WT but not KO males reduced during postnatal development to be significantly lower compared with females at P21. POA ERβ levels were higher in WT males than in WT females, while those in KO males were lower than in WT males and similar to those in WT and KO females at P0-P21. POA kisspeptin expression was female-biased in WT mice, while levels in KO females were lower compared with WT females and similar to those in WT and KO males. ARC kisspeptin levels were equivalent among groups at E15.5-P0. At P7-P21, ARC levels in WT but not KO males became lower compared with WT females. Diethylstilbestrol exposure during P0-P6 and P7-P13 increased POA PR and ERβ, and decreased POA ERα and ARC kisspeptin levels at P7 and/or P14 in both sexes of KO mice. These data further understanding of gonadal hormone action on neuronal marker expression during brain sexual development.

Copyright © 2019 Elsevier B.V. All rights reserved.

KEYWORDS: Brain sex differentiation; Estrogen receptors; Gonadal hormones; Kisspeptin; Progesterone receptor PMID: 30776325 DOI: 10.1016/j.brainres.2019.02.016

Development of the Basal Hypothalamus through Anisotropic Growth

J Neuroendocrinol. 2019 May 3:e12727. doi: 10.1111/jne.12727. [Epub ahead of print]

Fu T1, Pearson C1, Towers M1, Placzek M1.

The adult hypothalamus is subdivided into distinct domains: pre-optic, anterior, tuberal and mammillary. Each domain harbours an array of neurons that act together to regulate homeostasis. The embryonic origins and development of hypothalamic neurons, however, remains enigmatic. Here we summarise recent studies in model organisms that challenge current views of hypothalamic development, which traditionally have attempted to map adult domains to correspondingly-located embryonic domains that expand isotropically. Instead, new studies indicate that hypothalamic neurons arise from progenitor cells that undergo anisotropic growth in different dimensions. Here we describe how a multipotent Shh/ Fgf10-expressing progenitor population gives rise to progenitors that grow anisotropically, expanding to a greater extent than other progenitors and giving rise to cells throughout the basal hypothalamus. Further, Shh/Fgf10+ive -derived progenitors grow sequentially in different directions from the multipotent Shh/ Fgf10 population: first, a subset displaced rostrally give rise to anterior-ventral/tuberal neuronal progenitors, then a subset displaced caudally give rise to mammillary neuronal progenitors; finally, a subset(s) displaced ventrally give rise to tuberal infundibular glial progenitors. As this occurs, stable populations of Shh+ive and Fgf10+ive progenitors form. We describe current understanding of the mechanisms that induce Shh/Fgf10+ive progenitors, and begin to direct their differentiation to anterior-ventral/tuberal neuronal progenitors, mammillary neuronal progenitors and tuberal infundibular progenitors. Together these studies suggest a new model for hypothalamic development that we term the Anisotropic growth model. We discuss the implications of the model for understanding the origins of adult hypothalamic neurons. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS: Fgf10; Shh; anisotropic growth; development; hypothalamus; prechordal mesendoderm; progenitor PMID: 31050853 DOI: 10.1111/jne.12727

Anatomy, development, and plasticity of the neurosecretory hypothalamus in zebrafish

Cell Tissue Res. 2019 Jan;375(1):5-22. doi: 10.1007/s00441-018-2900-4. Epub 2018 Aug 14. Nagpal J1, Herget U2, Choi MK1, Ryu S3.

The paraventricular nucleus (PVN) of the hypothalamus harbors diverse neurosecretory cells with critical physiological roles for the homeostasis. Decades of research in rodents have provided a large amount of information on the anatomy, development, and function of this important hypothalamic nucleus. However, since the hypothalamus lies deep within the brain in mammals and is difficult to access, many questions regarding development and plasticity of this nucleus still remain. In particular, how different environmental conditions, including stress exposure, shape the development of this important nucleus has been difficult to address in animals that develop in utero. To address these open questions, the transparent larval zebrafish with its rapid external development and excellent genetic toolbox offers exciting opportunities. In this review, we summarize recent information on the anatomy and development of the neurosecretory preoptic area (NPO), which represents a similar structure to the mammalian PVN in zebrafish. We will then review recent studies on the development of different cell types in the neurosecretory hypothalamus both in mouse and in fish. Lastly, we discuss stress-induced plasticity of the PVN mainly discussing the data obtained in rodents, but pointing out tools and approaches available in zebrafish for future studies. This review serves as a primer for the currently available information relevant for studying the development and plasticity of this important brain region using zebrafish.

KEYWORDS: Hypothalamus; Paraventricular nucleus; Stress; Zebrafish PMID: 30109407 DOI: 10.1007/s00441-018-2900-4


Novel insights into the spatial and temporal complexity of hypothalamic organization through precision methods allowing nanoscale resolution

Alpár A & Harkany T. (2018). Novel insights into the spatial and temporal complexity of hypothalamic organization through precision methods allowing nanoscale resolution. J. Intern. Med. , , . PMID: 30027599 DOI.

Alpár A1,2, Harkany T3,4. Author information Abstract The mammalian hypothalamus contains an astounding heterogeneity of neurons to achieve its role in coordinating central responses to virtually any environmental stressor over the life-span of an individual. Therefore, while core features of intrahypothalamic neuronal modalities and wiring patterns are stable during vertebrate evolution, integration of the hypothalamus into hierarchical brain-wide networks evolved to coordinate its output with emotionality, cognition and conscious decision-making. The advent of single-cell technologies represents a recent milestone in the study of hypothalamic organization by allowing the dissection of cellular heterogeneity and establishing causality between opto- and chemogenetic activity modulation of molecularly-resolved neuronal contingents and specific behaviours. Thus, organizational rules to accumulate an unprecedented variety of hierarchical neuroendocrine command networks into a minimal brain volume are being unravelled. Here, we review recent understanding at nanoscale resolution on how neuronal heterogeneity in the mammalian hypothalamus underpins the diversification of hormonal and synaptic output and keeps those sufficiently labile for continuous adaptation to meet environmental demands. Particular emphasis is directed towards the dissection of neuronal circuitry for aggression and food intake. Mechanistic data encompass cell identities, synaptic connectivity within and outside the hypothalamus to link vegetative and conscious levels of innate behaviours, and context- and circadian rhythm-dependent rules of synaptic neurophysiology to distinguish hypothalamic foci that either tune the body's metabolic set-point or specify behaviours. Consequently, novel insights emerge to explain the evolutionary advantages of non-laminar organization for neuroendocrine circuits coincidently using fast neurotransmitters and neuropeptides. These are then accrued into novel therapeutic principles that meet therapeutic criteria for human metabolic diseases. KEYWORDS: cell state; hormone; identity switch; magnocellular and parvocellular systems; neuropeptide PMID: 30027599 DOI: 10.1111/joim.12815

Regulation of feeding by somatostatin neurons in the tuberal nucleus

Luo SX, Huang J, Li Q, Mohammad H, Lee CY, Krishna K, Kok AM, Tan YL, Lim JY, Li H, Yeow LY, Sun J, He M, Grandjean J, Sajikumar S, Han W & Fu Y. (2018). Regulation of feeding by somatostatin neurons in the tuberal nucleus. Science , 361, 76-81. PMID: 29976824 DOI.

Luo SX1, Huang J2, Li Q1,3, Mohammad H1, Lee CY1, Krishna K4, Kok AM1, Tan YL1, Lim JY1, Li H1, Yeow LY1, Sun J2, He M5, Grandjean J1, Sajikumar S4, Han W1, Fu Y6,4. Author information Abstract The tuberal nucleus (TN) is a surprisingly understudied brain region. We found that somatostatin (SST) neurons in the TN, which is known to exhibit pathological or cytological changes in human neurodegenerative diseases, play a crucial role in regulating feeding in mice. GABAergic tuberal SST (TNSST) neurons were activated by hunger and by the hunger hormone, ghrelin. Activation of TNSST neurons promoted feeding, whereas inhibition reduced it via projections to the paraventricular nucleus and bed nucleus of the stria terminalis. Ablation of TNSST neurons reduced body weight gain and food intake. These findings reveal a previously unknown mechanism of feeding regulation that operates through orexigenic TNSST neurons, providing a new perspective for understanding appetite changes. Comment in A new brain circuit in feeding control. [Science. 2018] PMID: 29976824 DOI: 10.1126/science.aar4983


Development of the hypothalamus: conservation, modification and innovation

Development. 2017 May 1;144(9):1588-1599. doi: 10.1242/dev.139055.

Xie Y1, Dorsky RI2.


The hypothalamus, which regulates fundamental aspects of physiological homeostasis and behavior, is a brain region that exhibits highly conserved anatomy across vertebrate species. Its development involves conserved basic mechanisms of induction and patterning, combined with a more plastic process of neuronal fate specification, to produce brain circuits that mediate physiology and behavior according to the needs of each species. Here, we review the factors involved in the induction, patterning and neuronal differentiation of the hypothalamus, highlighting recent evidence that illustrates how changes in Wnt/β-catenin signaling during development may lead to species-specific form and function of this important brain structure. KEYWORDS: Adult neurogenesis; Evolution; Hypothalamus; Wnt

PMID: 28465334 PMCID: PMC5450842 [Available on 2018-05-01] DOI: 10.1242/dev.139055


Hypothalamus as an endocrine organ

Compr Physiol. 2015 Jan;5(1):217-53. doi: 10.1002/cphy.c140019.

Clarke IJ.


The endocrine hypothalamus constitutes those cells which project to the median eminence and secrete neurohormones into the hypophysial portal blood to act on cells of the anterior pituitary gland. The entire endocrine system is controlled by these peptides. In turn, the hypothalamic neuroendocrine cells are regulated by feedback signals from the endocrine glands and other circulating factors. The neuroendocrine cells are found in specific regions of the hypothalamus and are regulated by afferents from higher brain centers. Integrated function is clearly complex and the networks between and amongst the neuroendocrine cells allows fine control to achieve homeostasis. The entry of hormones and other factors into the brain, either via the cerebrospinal fluid or through fenestrated capillaries (in the basal hypothalamus) is important because it influences the extent to which feedback regulation may be imposed. Recent evidence of the passage of factors from the pars tuberalis and the median eminence casts a new layer in our understanding of neuroendocrine regulation. The function of neuroendocrine cells and the means by which pulsatile secretion is achieved is best understood for the close relationship between gonadotropin releasing hormone and luteinizing hormone, which is reviewed in detail. The secretion of other neurohormones is less rigid, so the relationship between hypothalamic secretion and the relevant pituitary hormones is more complex.

© 2015 American Physiological Society.

PMID 25589270

Editorial: Development of the hypothalamus

Front Neuroanat. 2015 Jun 23;9:83. doi: 10.3389/fnana.2015.00083. eCollection 2015.

Alvarez-Bolado G1, Grinevich V2, Puelles L3.

The hypothalamus is the region of the brain in charge of homeostasis as well as homeostatic behaviors like eating and drinking. The anatomical, connectional and physiological complexity of this region matches the importance and intricacy of its functions. Perhaps because of this, research on the developing hypothalamus has lagged behind that on the cortex or hippocampus.

  • Many workers are turning to the updated prosomeric model as an instrument for morphologic and causal interpretation. The model proposes that the hypothalamus is the rostralmost part of the neural tube, since the developmental forebrain length axis ends in the terminal wall of the hypothalamus (i.e., the telencephalon is a dorsal outgrowth of the alar hypothalamus).
  • The resulting peduncular and terminal hypothalamic subdivisions of the rostral part of the neural tube are admittedly divergent with those traditionally taught under the columnar viewpoint.

KEYWORDS: MCH; Notch; Shh; circadian; oxytocin; prosomeric; thyroid; zebrafish

PMID 26157363

A new scenario of hypothalamic organization: rationale of new hypotheses introduced in the updated prosomeric model

Front Neuroanat. 2015 Mar 19;9:27. doi: 10.3389/fnana.2015.00027. eCollection 2015.

Puelles L1, Rubenstein JL2.


In this essay, we aim to explore in depth the new concept of the hypothalamus that was presented in the updated prosomeric model (Puelles et al., 2012b; Allen Developing Mouse Brain Atlas). Initial sections deal with the antecedents of prosomeric ideas represented by the extensive literature centered on the alternative columnar model of Herrick (1910), Kuhlenbeck (1973) and Swanson (1992, 2003); a detailed critique explores why the columnar model is not helpful in the search for causal developmental explanations. In contrast, the emerging prosomeric scenario visibly includes many possibilities to propose causal explanations of hypothalamic structure relative to both anteroposterior and dorsoventral patterning mechanisms, and insures the possibility to compare hypothalamic histogenesis with that of more caudal parts of the brain. Next the four major changes introduced in the organization of the hypothalamus on occasion of the updated model are presented, and our rationale for these changes is explored in detail. It is hoped that this example of morphological theoretical analysis may be useful for readers interested in brain models, or in understanding why models may need to change in the quest for higher consistency. KEYWORDS: acroterminal domain; anteroposterior pattern; dorsoventral pattern; genoarchitecture; length axis; peduncular hypothalamus; terminal hypothalamus; tracts

PMID 25852489

About Oxytocin Hormone
Structure Function
  • polypeptide hormone 9 amino acids
  • first peptide hormone to be sequenced and synthesized (1953).
  • single gene arose by duplication of vasopressin gene
    • vasopressin is 9 amino acid hormone constricts blood vessels and retain body water.
  • hormone degraded by GIT.
  • hormone cannot pass the blood-brain barrier.
  • Birth - increase in uterine muscle tone and strength of contractions.
  • Lactation - hormone released in response to the baby suckling.
  • stimulates contraction of muscle cells around mammary glands.
  • neural effects
Links: Birth | Hypothalamus | Endocrine | Mammary Gland | Milk | image - Oxytocin receptor pathways

Role of developmental factors in hypothalamic function

Front Neuroanat. 2015 Apr 21;9:47. doi: 10.3389/fnana.2015.00047. eCollection 2015.

Biran J1, Tahor M1, Wircer E1, Levkowitz G1.


The hypothalamus is a brain region which regulates homeostasis by mediating endocrine, autonomic and behavioral functions. It is comprised of several nuclei containing distinct neuronal populations producing neuropeptides and neurotransmitters that regulate fundamental body functions including temperature and metabolic rate, thirst and hunger, sexual behavior and reproduction, circadian rhythm, and emotional responses. The identity, number and connectivity of these neuronal populations are established during the organism's development and are of crucial importance for normal hypothalamic function. Studies have suggested that developmental abnormalities in specific hypothalamic circuits can lead to obesity, sleep disorders, anxiety, depression and autism. At the molecular level, the development of the hypothalamus is regulated by transcription factors (TF), secreted growth factors, neuropeptides and their receptors. Recent studies in zebrafish and mouse have demonstrated that some of these molecules maintain their expression in the adult brain and subsequently play a role in the physiological functions that are regulated by hypothalamic neurons. Here, we summarize the involvement of some of the key developmental factors in hypothalamic development and function by focusing on the mouse and zebrafish genetic model organisms. KEYWORDS: Otp; PAC1; SF-1; SIM1; homeostasis; neuroendocrine; neuropeptides; zebrafish model system

PMID 25954163


Development of the HPA axis: Where and when do sex differences manifest?

Front Neuroendocrinol. 2014 Mar 13. pii: S0091-3022(14)00036-3. doi: 10.1016/j.yfrne.2014.03.002. [Epub ahead of print]

Panagiotakopoulos L1, Neigh GN2.


Sex differences in the response to stress contribute to sex differences in somatic, neurological, and psychiatric diseases. Despite a growing literature on the mechanisms that mediate sex differences in the stress response, the ontogeny of these differences has not been comprehensively reviewed. This review focuses on the development of the hypothalamic-pituitary-adrenal (HPA) axis, a key component of the body's response to stress, and examines the critical points of divergence during development between males and females. Insight gained from animal models and clinical studies are presented to fully illustrate the current state of knowledge regarding sex differences in response to stress over development. An appreciation for the developmental timelines of the components of the HPA axis will provide a foundation for future areas of study by highlighting both what is known and calling attention to areas in which sex differences in the development of the HPA axis have been understudied. Copyright © 2014 Elsevier Inc. All rights reserved. KEYWORDS: Adrenals, CRF, Development, Glucocorticoids, HPA axis, Hippocampus, Hormones, Hypothalamus, Pituitary, Sex

PMID 24631756

Development of the blood-brain barrier within the paraventricular nucleus of the hypothalamus: influence of fetal glucocorticoid excess

Brain Struct Funct. 2014 May 11. [Epub ahead of print]

Frahm KA1, Tobet SA.


The blood-brain barrier (BBB) is a critical contributor to brain function. To understand its development and potential function in different brain regions, the postnatal (P) BBB was investigated in the mouse cortex (CTX), lateral hypothalamus, and paraventricular nucleus of the hypothalamus (PVN). Brains were examined on postnatal days (P)12, P22 and P52 for BBB competency and for pericytes as key cellular components of the BBB demarcated by immunoreactive desmin. Glucocorticoid influences (excess dexamethasone; dex) during prenatal development were also assessed for their impact on the blood vessels within these regions postnatally. At P12, there was significantly more extravascular leakage of a low molecular weight dye (fluorescein isothiocyanate) in the CTX than within hypothalamic regions. For pericytes, there were low levels of desmin immunoreactivity at P12 that increased with age for all regions. There was more desmin immunoreactivity present in the PVN at each age examined. Fetal dex exposure resulted in decreased blood vessel density within the PVN at P20. In the CTX, dex exposure increased BBB competency, in contrast to the PVN where there was a decrease in BBB competency and increased pericyte presence. Overall, unique alterations in the functioning of the BBB within the PVN may provide a novel mechanism for fetal antecedent programming that may influence adult disorders.

PMID 24817635


Maps of the adult human hypothalamus

Surg Neurol Int. 2013 Apr 17;4(Suppl 3):S156-63. doi: 10.4103/2152-7806.110667. Print 2013.

Lemaire JJ, Nezzar H, Sakka L, Boirie Y, Fontaine D, Coste A, Coll G, Sontheimer A, Sarret C, Gabrillargues J, De Salles A. Source Univ Clermont 1, UFR Médecine, EA 7282, Image-Guided Clinical Neuroscience and Connectomics, Clermont-Ferrand, F-63001, France ; Service de Neurochirurgie, CHU Clermont-Ferrand, Clermont-Ferrand, F-63003, France. Abstract The human hypothalamus is a small deeply located region placed at the crossroad of neurovegetative, neuroendocrine, limbic, and optic systems. Although deep brain stimulation techniques have proven that it could be feasible to modulate these systems, targeting the hypothalamus and in particular specific nuclei and white bundles, is still challenging. Our goal was to make a synthesis of relevant topographical data of the human hypothalamus, under the form of magnetic resonance imaging maps useful for mastering its elaborated structure as well as its neighborhood. As from 1.5 Tesla, Inversion-Recovery sequence allows locating the hypothalamus and most of its components. Spotting hypothalamic compartments is possible according to specific landmarks: the anterior commissure, the mammillary bodies, the preoptic recess, the infundibular recess, the crest between the preoptic and the infundibular recesses, the optical tract, the fornix, and the mammillo-thalamic bundle. The identification of hypothalamus and most of its components could be useful to allow the quantification of local pathological processes and to target specific circuitry to alleviate severe symptoms, using physical or biological agents. KEYWORDS: Brain mapping, hypothalamus, inversion-recovery sequence, magnetic resonance imaging, stereotaxy

PMID 23682342


MRI atlas of the human hypothalamus

Neuroimage. 2012 Jan 2;59(1):168-80. doi: 10.1016/j.neuroimage.2011.07.013. Epub 2011 Jul 14.

Baroncini M, Jissendi P, Balland E, Besson P, Pruvo JP, Francke JP, Dewailly D, Blond S, Prevot V. Source Inserm, Jean-Pierre Aubert Research Center, U837, Development and Plasticity of the postnatal Brain, Univ Lille Nord de France, CHRU Lille, Department of Neurosurgery, Lille University Hospital, 59037 Lille cedex, France. Abstract Gaining new insights into the anatomy of the human hypothalamus is crucial for the development of new treatment strategies involving functional stereotactic neurosurgery. Here, using anatomical comparisons between histology and magnetic resonance images of the human hypothalamus in the coronal plane, we show that discrete gray and white hypothalamic structures are consistently identifiable by MRI. Macroscopic and microscopic images were used to precisely annotate the MRI sequences realized in the coronal plane in twenty healthy volunteers. MRI was performed on a 1.5 T scanner, using a protocol including T1-weighted 3D fast field echo, T1-weighted inversion-recovery, turbo spin echo and T2-weighted 2D fast field echo imaging. For each gray matter structure as well as for white matter bundles, the different MRI sequences were analyzed in comparison to each other. The anterior commissure and the fornix were often identifiable, while the mammillothalamic tract was more difficult to spot. Qualitative analyses showed that MRI could also highlight finer structures such as the paraventricular nucleus, the ventromedial nucleus of the hypothalamus and the infundibular (arcuate) nucleus, brain nuclei that play key roles in the regulation of food intake and energy homeostasis. The posterior hypothalamic area, a target for deep brain stimulation in the treatment of cluster headaches, was readily identified, as was the lateral hypothalamic area, which similar to the aforementioned hypothalamic nuclei, could be a putative target for deep brain stimulation in the treatment of obesity. Finally, each of the identified structures was mapped to Montreal Neurological Institute (MNI) space. Copyright © 2011 Elsevier Inc. All rights reserved.

PMID 21777680

Sonic hedgehog lineage in the mouse hypothalamus: from progenitor domains to hypothalamic regions

Neural Dev. 2012 Jan 20;7:4. doi: 10.1186/1749-8104-7-4.

Alvarez-Bolado G, Paul FA, Blaess S. Source Department of Neuroanatomy, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.


BACKGROUND: The hypothalamus is a brain region with essential functions for homeostasis and energy metabolism, and alterations of its development can contribute to pathological conditions in the adult, like hypertension, diabetes or obesity. However, due to the anatomical complexity of the hypothalamus, its development is not well understood. Sonic hedgehog (Shh) is a key developmental regulator gene expressed in a dynamic pattern in hypothalamic progenitor cells. To obtain insight into hypothalamic organization, we used genetic inducible fate mapping (GIFM) to map the lineages derived from Shh-expressing progenitor domains onto the four rostrocaudally arranged hypothalamic regions: preoptic, anterior, tuberal and mammillary. RESULTS: Shh-expressing progenitors labeled at an early stage (before embryonic day (E)9.5) contribute neurons and astrocytes to a large caudal area including the mammillary and posterior tuberal regions as well as tanycytes (specialized median eminence glia). Progenitors labeled at later stages (after E9.5) give rise to neurons and astrocytes of the entire tuberal region and in particular the ventromedial nucleus, but not to cells in the mammillary region and median eminence. At this stage, an additional Shh-expressing domain appears in the preoptic area and contributes mostly astrocytes to the hypothalamus. Shh-expressing progenitors do not contribute to the anterior region at any stage. Finally, we show a gradual shift from neurogenesis to gliogenesis, so that progenitors expressing Shh after E12.5 generate almost exclusively hypothalamic astrocytes. CONCLUSIONS: We define a fate map of the hypothalamus, based on the dynamic expression of Shh in the hypothalamic progenitor zones. We provide evidence that the large neurogenic Shh-expressing progenitor domains of the ventral diencephalon are continuous with those of the midbrain. We demonstrate that the four classical transverse zones of the hypothalamus have clearly defined progenitor domains and that there is little or no cell mixing between the tuberal and anterior or the preoptic and anterior hypothalamus. Finally, we show that, in the tuberal hypothalamus, neurons destined for every mediolateral level are produced during a period of days, in conflict with the current 'three-wave' model of hypothalamic neurogenesis. Our work sets the stage for a deeper developmental analysis of this complex and important brain region.

PMID 22264356


Development of Posterior Hypothalamic Neurons Enlightens a Switch in the Prosencephalic Basic Plan

In rats and mice, ascending and descending axons from neurons producing melanin-concentrating hormone (MCH) reach the cerebral cortex and spinal cord. However, these ascending and descending projections originate from distinct sub-populations expressing or not “Cocaine-and-Amphetamine-Regulated-Trans​cript”(CART) peptide. Using a BrdU approach, MCH cell bodies are among the very first generated in the hypothalamus, within a longitudinal cell cord made of earliest delaminating neuroblasts in the diencephalon and extending from the chiasmatic region to the ventral midbrain. This region also specifically expresses the regulatory genes Sonic hedgehog (Shh) and Nkx2.2.

The Krüppel-like factor 4 controls biosynthesis of thyrotropin-releasing hormone during hypothalamus development

Mol Cell Endocrinol. 2011 Feb 20;333(2):127-33. Epub 2010 Dec 21.

Pérez-Monter C, Martínez-Armenta M, Miquelajauregui A, Furlan-Magaril M, Varela-Echavarría A, Recillas-Targa F, May V, Charli JL, Pérez-Martínez L. Source Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62271, Mexico.


Embryonic neurogenesis is controlled by the activation of specific genetic programs. In the hypothalamus, neuronal thyrotropin-releasing hormone (TRH) populations control important physiological process, including energy homeostasis and autonomic function; however, the genetic program leading to the TRH expression is poorly understood. Here, we show that the Klf4 gene, encoding the transcription factor Krüppel-like factor 4 (Klf4), was expressed in the rat hypothalamus during development and regulated Trh expression. In rat fetal hypothalamic cells Klf4 regulated Trh promoter activity through CACCC and GC motifs present on the Trh gene promoter. Accordingly, hypothalamic Trh expression was down-regulated at embryonic day 15 in the Klf4(-/-) mice resulting in diminished bioactive peptide levels. Although at the neonatal stage the Trh transcript levels of the Klf4(-/-) mice were normal, the reduction in peptide levels persisted. Thus, our data indicate that Klf4 plays a key role in the maturation of TRH expression in hypothalamic neurons. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PMID 21182892

Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus

Toxicol Appl Pharmacol. 2011 Apr 1;252(1):36-46. Epub 2011 Jan 26.

Dickerson SM, Cunningham SL, Gore AC. Source Center for Molecular and Cellular Toxicology, Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX 78712, USA.


Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; or estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor α (ERα) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ERα, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA(B) receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGFα. Collectively, these results suggest that the disrupted sexual differentiation of the POA by prenatal EDC exposures is already evident as early as the day after birth, effects that may change the trajectory of postnatal development and compromise adult reproductive function.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID 21277884

Neuropeptide Signaling Differentially Affects Phase Maintenance and Rhythm Generation in SCN and Extra-SCN Circadian Oscillators

PLoS One. 2011 Apr 29;6(4):e18926.

Hughes AT, Guilding C, Piggins HD. Source Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.


Circadian rhythms in physiology and behavior are coordinated by the brain's dominant circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Vasoactive intestinal polypeptide (VIP) and its receptor, VPAC(2), play important roles in the functioning of the SCN pacemaker. Mice lacking VPAC(2) receptors (Vipr2(-/-)) express disrupted behavioral and metabolic rhythms and show altered SCN neuronal activity and clock gene expression. Within the brain, the SCN is not the only site containing endogenous circadian oscillators, nor is it the only site of VPAC(2) receptor expression; both VPAC(2) receptors and rhythmic clock gene/protein expression have been noted in the arcuate (Arc) and dorsomedial (DMH) nuclei of the mediobasal hypothalamus, and in the pituitary gland. The functional role of VPAC(2) receptors in rhythm generation and maintenance in these tissues is, however, unknown. We used wild type (WT) and Vipr2(-/-) mice expressing a luciferase reporter (PER2::LUC) to investigate whether circadian rhythms in the clock gene protein PER2 in these extra-SCN tissues were compromised by the absence of the VPAC(2) receptor. Vipr2(-/-) SCN cultures expressed significantly lower amplitude PER2::LUC oscillations than WT SCN. Surprisingly, in Vipr2(-/-) Arc/ME/PT complex (Arc, median eminence and pars tuberalis), DMH and pituitary, the period, amplitude and rate of damping of rhythms were not significantly different to WT. Intriguingly, while we found WT SCN and Arc/ME/PT tissues to maintain a consistent circadian phase when cultured, the phase of corresponding Vipr2(-/-) cultures was reset by cull/culture procedure. These data demonstrate that while the main rhythm parameters of extra-SCN circadian oscillations are maintained in Vipr2(-/-) mice, the ability of these oscillators to resist phase shifts is compromised. These deficiencies may contribute towards the aberrant behavior and metabolism associated with Vipr2(-/-) animals. Further, our data indicate a link between circadian rhythm strength and the ability of tissues to resist circadian phase resetting.

PMID 21559484

Perinatal photoperiod imprints the circadian clock

Christopher M Ciarleglio, John C Axley, Benjamin R Strauss, Karen L Gamble and Douglas G McMahon doi:10.1038/nn.2699

This study finds that mice's biological clocks are permanently influenced by the seasonal photoperiod at and after birth. In mice raised under summer-like light periods, rhythmic gene expression in the suprachiasmatic nucleus was tightly correlated with lights-off under both summer- and winter-like cycles. In 'winter-born' mice, these rhythms were tightly correlated only under winter-like light cycles.

Nature Neuroscience 14, 25–27 (2011) doi:10.1038/nn.2699 Received 24 August 2010 Accepted 21 October 2010 Published online 05 December 2010


Oxytocin-Gly-Lys-Arg: a novel cardiomyogenic peptide

PLoS One. 2010 Oct 26;5(10):e13643.

Danalache BA, Gutkowska J, Slusarz MJ, Berezowska I, Jankowski M.

Research Centre, Centre Hospitalier de l'Université de Montréal - Hôtel-Dieu, Montreal, Quebec, Canada. Abstract BACKGROUND: Oxytocin (OT), synthesized in the heart, has the ability to heal injured hearts and to promote cardiomyogenesis from stem cells. Recently, we reported that the OT-GKR molecule, a processing intermediate of OT, potently increased the spontaneous formation of cardiomyocytes (CM) in embryonic stem D3 cells and augmented glucose uptake in newborn rat CM above the level stimulated by OT. In the present experiments, we investigated whether OT-GKR exists in fetal and newborn rodent hearts, interacts with the OT receptors (OTR) and primes the generation of contracting cells expressing CM markers in P19 cells, a model for the study of early heart differentiation.

METHODOLOGY/PRINCIPAL FINDINGS: High performance liquid chromatography of newborn rat heart extracts indicated that OT-GKR was a dominant form of OT. Immunocytochemistry of mouse embryos (embryonic day 15) showed cardiac OT-GKR accumulation and OTR expression. Computerized molecular modeling revealed OT-GKR docking to active OTR sites and to V1a receptor of vasopressin. In embryonic P19 cells, OT-GKR induced contracting cell colonies and ventricular CM markers more potently than OT, an effect being suppressed by OT antagonists and OTR-specific small interfering (si) RNA. The V1a receptor antagonist and specific si-RNA also significantly reduced OT-GKR-stimulated P19 contracting cells. In comparison to OT, OT-GKR induced in P19 cells less α-actinin, myogenin and MyoD mRNA, skeletal muscle markers.

CONCLUSIONS/SIGNIFICANCE: These results raise the possibility that C-terminally extended OT molecules stimulate CM differentiation and contribute to heart growth during fetal life.

PMID: 21048978

Interactions of the Circadian CLOCK System and the HPA Axis

Trends Endocrinol Metab. 2010 May;21(5):277-86. Epub 2010 Jan 26.

Nader N, Chrousos GP, Kino T.

Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Abstract Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic-pituitary-adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions. In this review, we summarize the mutual physiologic interactions between the circadian CLOCK system and the HPA axis, and discuss their clinical implications.

PMID: 20106676


Vertebrate retina and hypothalamus development

Wiley Interdiscip Rev Syst Biol Med. 2009 Nov-Dec;1(3):380-9.

Byerly MS, Blackshaw S. Source Department of Neuroscience, Neurology and Ophthalamology, Johns Hopkins School of Medicine, Baltimore, MD, USA.


The vertebrate retina and hypothalamus, which emerge from adjacent regions of the ventral diencephalon, provide accessible experimental systems for analysis of the molecular mechanisms by which neuronal subtype diversity is specified, and how this neuronal subtype diversity regulates perception and behavior. Although the retina emerges as a lateral extension of the hypothalamus prior to the onset of neurogenesis, the retina and hypothalamus go on to eventually be comprised of almost entirely different cell types, and differ extensively in the spatial organization, function, and connectivity of these cells. Despite these differences in cell composition, there are a number of mechanistic and molecular similarities in the process of cell fate specification in both organs, including a stereotyped temporal sequence in which major cell types are generated. Although a handful of genes have been identified in both systems that direct cell fate specification, many more remain to be characterized, and large numbers of candidate genes have been identified in recent high-throughput screens, particularly in retina. Experimental challenges for the near future include functional analysis of the genes identified so far, and the use of the molecular pathways gained from analysis of the development of specific neuronal lineages to study the contribution of these cells to perception and behavior.

PMID 20836003

Genetic regulation of pituitary gland development in human and mouse

Endocr Rev. 2009 Dec;30(7):790-829. Epub 2009 Oct 16.

Kelberman D, Rizzoti K, Lovell-Badge R, Robinson IC, Dattani MT.

Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. Abstract Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke's pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans.

PMID 19837867


Oxytocin in cardiac ontogeny

Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13074-9. Epub 2004 Aug 17.

Jankowski M, Danalache B, Wang D, Bhat P, Hajjar F, Marcinkiewicz M, Paquin J, McCann SM, Gutkowska J.

Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Hôtel-Dieu, 3840 Rue Saint-Urbain, Montréal, QC, Canada H2W 1T8. Abstract Previous studies demonstrated the presence of oxytocin (OT) and oxytocin receptors (OTRs) in the heart. The present work provides results supporting a potential role of OT in cardiomyogenesis. Here, we show a maximal OT and OTR protein level in the developing rat heart at day 21 of gestation and postnatal days 1-4, when cardiac myocytes are at a stage of intense hyperplasia. Between postnatal days 1 and 66, OT decreased linearly in all heart chambers (4.1- to 6.6-fold). Correspondingly, immunocytochemistry demonstrated that OTRs, which were eminent in postnatal cardiomyocytes, declined with age to low levels in adults. Interestingly, in coronary vasculature, OTRs developed in endothelial cells at postnatal days 12 and 22 and achieved a plateau in adult rats. These findings suggest that OT can be involved in developmental formation of the coronary vessels. In vivo, the OT/OTR system in the fetal heart was sensitive to the actions of retinoic acid (RA), recognized as a major cardiac morphogen. RA treatment produced a significant increase (2- to 3-fold) both in the OT concentration and in the OT mRNA levels. Ex vivo, an OT antagonist inhibited RA-mediated cardiomyocyte differentiation of P19 embryonic stem cells. The decline of cardiac OT expression from infancy to adulthood of the rat and changes in cell types expressing OTR indicate a dynamic regulation of the OT system in the heart rather than constitutive expression. The results support the hypothesis that RA induces cardiomyogenesis by activation of the cardiac OT system.

Copyright 2004 The National Academy of Sciencs of the USA PMID: 15316117


Oxytocin and vasopressin receptors in human and uterine myomas during menstrual cycle and early pregnancy

Hum Reprod Update. 1998 Sep-Oct;4(5):594-604.

Fuchs AR, Behrens O, Maschek H, Kupsch E, Einspanier A.

Department of Obstetrics and Gynecology, Cornell University Medical College, New York, NY 10021, USA. Abstract The purpose of this study was to determine the specificity and concentration of oxytocin (OT) and arginine vasopressin (AVP) binding sites in non-pregnant (NP) human and rhesus monkey endometrium, myometrium and fibromyomas, and to determine the cellular localization of OT receptor (OTR). Besides [3H]AVP, [125I]LVA, a specific VP1 receptor subtype antagonist, was used to determine vasopressin receptor (VPR) concentrations. Samples were obtained from 42 pre-menopausal and three pregnant women (5, 13 and 35 weeks gestation), and several NP and pregnant monkeys. Specificity of binding was assessed in competition experiments with unlabelled agonists and antagonists of known pharmacological potency. Cellular localization of OTR was determined by immunohistochemistry. In NP human uterine tissues, [3H]AVP was bound with higher affinity and greater binding capacity than [3H]OT, whereas in pregnant women and in NP and pregnant rhesus monkeys, uterine OT binding capacity was greater. OT and AVP binding sites discriminated very poorly between OT and AVP; [125I]LVA binding sites were more selective than [3H]AVP. Their ligand specificity and binding kinetics indicated the presence of two distinct populations of binding sites for OT and AVP in primate uterus. Endometrium of NP women and monkeys had low OTR and VPR concentrations. Myometrial and endometrial OTR and VPR were down-regulated in midcycle and in early human pregnancy, they were up-regulated in the secretory phase and second half of pregnancy. Immunoreactive OTR in NP uterus was localized in patches of myometrial muscle cells and small numbers of endometrial epithelial cells.

PMID: 10027613


Castro-Dufourny I, Carrasco R, Prieto R & Pascual JM. (2017). Jean Camus and Gustave Roussy: pioneering French researchers on the endocrine functions of the hypothalamus. Pituitary , 20, 409-421. PMID: 28265842 DOI.

French physicians Jean Camus (1872–1924) and Gustave Roussy (1874–1948) were the first authors to undertake systematic, controlled observations of the effects of localized injuries to the basal hypothalamus in dogs and cats by pricking the infundibulo-tuberal region (ITR) with a heated needle.

Their results challenged the dominant doctrine of hypopituitarism as cause of diabetes insipidus and adiposogenital dystrophy that derived from the experiments performed by Paulescu and Cushing a decade earlier.