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      Ontogenesis of peptidergic neurons within the genoarchitectonic map of the mouse hypothalamus

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          Abstract

          During early development, the hypothalamic primordium undergoes anteroposterior and dorsoventral regionalization into diverse progenitor domains, each characterized by a differential gene expression code. The types of neurons produced selectively in each of these distinct progenitor domains are still poorly understood. Recent analysis of the ontogeny of peptidergic neuronal populations expressing Sst, Ghrh, Crh and Trh mRNAs in the mouse hypothalamus showed that these cell types originate from particular dorsoventral domains, characterized by specific combinations of gene markers. Such analysis implies that the differentiation of diverse peptidergic cell populations depends on the molecular environment where they are born. Moreover, a number of these peptidergic neurons were observed to migrate radially and/or tangentially, invading different adult locations, often intermingled with other cell types. This suggests that a developmental approach is absolutely necessary for the understanding of their adult distribution. In this essay, we examine comparatively the ontogenetic hypothalamic topography of twelve additional peptidergic populations documented in the Allen Developmental Mouse Brain Atlas, and discuss shared vs. variant aspects in their apparent origins, migrations and final distribution, in the context of the respective genoarchitectonic backgrounds. This analysis should aid ulterior attempts to explain causally the development of neuronal diversity in the hypothalamus, and contribute to our understanding of its topographic complexity in the adult.

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          Forebrain gene expression domains and the evolving prosomeric model.

          The prosomeric model attributes morphological meaning to gene expression patterns and other data in the forebrain. It divides this territory into the same transverse segments (prosomeres) and longitudinal zones in all vertebrates. The axis and longitudinal zones of this model are widely accepted but controversy subsists about the number of prosomeres and their nature as segments. We describe difficulties encountered in establishing continuity between prosomeric limits postulated in the hypothalamus and intra-telencephalic limits. Such difficulties throw doubt on the intersegmental nature of these limits. We sketch a simplified model, in which the secondary prosencephalon (telencephalon plus hypothalamus) is a complex protosegment not subdivided into prosomeres, which exhibits patterning singularities. By contrast, we continue to postulate that prosomeres p1-p3 (i.e. the pretectum, thalamus and prethalamus) are the caudal forebrain.
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            The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.

            The thyroid-specific enhancer-binding protein (T/ebp) gene was disrupted by homologous recombination in embryonic stem cells to generate mice lacking T/EBP expression. Heterozygous animals developed normally, whereas mice homozygous for the disrupted gene were born dead and lacked the lung parenchyma. Instead, they had a rudimentary bronchial tree associated with an abnormal epithelium in their pleural cavities. Furthermore, the homozygous mice had no thyroid gland but had a normal parathyroid. In addition, extensive defects were found in the brain of the homozygous mice, especially in the ventral region of the forebrain. The entire pituitary, including the anterior, intermediate, and posterior pituitary, was also missing. In situ hybridization showed that the T/ebp gene is expressed in the normal thyroid, lung bronchial epithelium, and specific areas of the forebrain during early embryogenesis. These results establish that the expression of T/EBP, a transcription factor known to control thyroid-specific gene transcription, is also essential for organogenesis of the thyroid, lung, ventral forebrain, and pituitary.
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              A genomic atlas of mouse hypothalamic development.

              The hypothalamus is a central regulator of many behaviors that are essential for survival, such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, we performed microarray analysis at 12 different developmental time points. We then conducted developmental in situ hybridization for 1,045 genes that were dynamically expressed over the course of hypothalamic neurogenesis. We identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis and constructed a detailed molecular atlas of the developing hypothalamus. As a proof of concept of the utility of these data, we used these markers to analyze the phenotype of mice in which Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium and found that Shh is essential for anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology and dysfunction.
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                Author and article information

                Contributors
                Journal
                Front Neuroanat
                Front Neuroanat
                Front. Neuroanat.
                Frontiers in Neuroanatomy
                Frontiers Media S.A.
                1662-5129
                12 January 2015
                2014
                : 8
                : 162
                Affiliations
                [1] 1Department of Medical Sciences, School of Medicine and Institute for Research in Neurological Disabilities, University of Castilla-La Mancha Albacete, Spain
                [2] 2Department of Human Anatomy and Psychobiology, University of Murcia, School of Medicine and IMIB (Instituto Murciano de Investigación Biosanitaria) Murcia, Spain
                Author notes

                Edited by: Gonzalo Alvarez-Bolado, University of Heidelberg, Germany

                Reviewed by: Stuart Tobet, Colorado State University, USA; Gonzalo Alvarez-Bolado, University of Heidelberg, Germany

                *Correspondence: Carmen Díaz, Department of Medical Sciences, School of Medicine and Institute for Research in Neurological Disabilities, University of Castilla-La Mancha Almansa Street, 14 Albacete 02006, Spain e-mail: Carmen.Diaz@ 123456uclm.es

                This article was submitted to the journal Frontiers in Neuroanatomy.

                Article
                10.3389/fnana.2014.00162
                4290630
                25628541
                1705760b-0913-4fda-995d-b6e9a5598e5d
                Copyright © 2015 Díaz, Morales-Delgado and Puelles.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 October 2014
                : 12 December 2014
                Page count
                Figures: 5, Tables: 3, Equations: 0, References: 96, Pages: 19, Words: 14534
                Categories
                Neuroscience
                Original Research Article

                Neurosciences
                hypothalamus,neuropeptides,genoarchitecture,progenitor areas,migrations
                Neurosciences
                hypothalamus, neuropeptides, genoarchitecture, progenitor areas, migrations

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