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Cited by 11Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesNeuroinflammation and Neurodegeneration Mechanisms

Reductions in hypothalamic Gfap expression, glial cells and α-tanycytes in lean and hypermetabolic Gnasxl-deficient mice

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Holmes, Andrew P., Wong, Shi Quan, Pulix, Michela, Johnson, Kirsty, Horton, Niamh S., Thomas, Patricia, de Magalhães, João Pedro, Plagge, Antonius·2016·Molecular Brain
DOI 10.1186/s13041-016-0219-1PMC PMC4832494
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Abstract

BACKGROUND: Neuronal and glial differentiation in the murine hypothalamus is not complete at birth, but continues over the first two weeks postnatally. Nutritional status and Leptin deficiency can influence the maturation of neuronal projections and glial patterns, and hypothalamic gliosis occurs in mouse models of obesity. Gnasxl constitutes an alternative transcript of the genomically imprinted Gnas locus and encodes a variant of the signalling protein Gαs, termed XLαs, which is expressed in defined areas of the hypothalamus. Gnasxl-deficient mice show postnatal growth retardation and undernutrition, while surviving adults remain lean and hypermetabolic with increased sympathetic nervous system (SNS) activity. Effects of this knock-out on the hypothalamic neural network have not yet been investigated. RESULTS: RNAseq analysis for gene expression changes in hypothalami of Gnasxl-deficient mice indicated Glial fibrillary acid protein (Gfap) expression to be significantly down-regulated in adult samples. Histological analysis confirmed a reduction in Gfap-positive glial cell numbers specifically in the hypothalamus. This reduction was observed in adult tissue samples, whereas no difference was found in hypothalami of postnatal stages, indicating an adaptation in adult Gnasxl-deficient mice to their earlier growth phenotype and hypermetabolism. Especially noticeable was a loss of many Gfap-positive α-tanycytes and their processes, which form part of the ependymal layer that lines the medial and dorsal regions of the 3(rd) ventricle, while β-tanycytes along the median eminence (ME) and infundibular recesses appeared unaffected. This was accompanied by local reductions in Vimentin and Nestin expression. Hypothalamic RNA levels of glial solute transporters were unchanged, indicating a potential compensatory up-regulation in the remaining astrocytes and tanycytes. CONCLUSION: Gnasxl deficiency does not directly affect glial development in the hypothalamus, since it is expressed in neurons, and Gfap-positive astrocytes and tanycytes appear normal during early postnatal stages. The loss of Gfap-expressing cells in adult hypothalami appears to be a consequence of the postnatal undernutrition, hypoglycaemia and continued hypermetabolism and leanness of Gnasxl-deficient mice, which contrasts with gliosis observed in obese mouse models. Since α-tanycytes also function as adult neural progenitor cells, these findings might indicate further developmental abnormalities in hypothalamic formations of Gnasxl-deficient mice, potentially including neuronal composition and projections.

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  • Brain RNA-seq from a Gnasxl-deficient mouse (M156) overlapped with FPbrown, a coexpression module (padj = 5.4 × 10−9) enriched for genes involved in oxidative phosphorylation and mitochondrial translation.

    “In another example, brain RNA-seq from a Gnasxl-deficient mouse (Holmes et al., 2016) (M156) overlapped with FPbrown, a coexpression module (padj = 5.4 × 10−9) enriched for genes involved in oxidative phosphorylation and mitochondrial translation.”

    From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Holmes et al., 2016

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Authors
Holmes, A. P., Wong, S. Q., Pulix, M., Johnson, K., Horton, N. S., Thomas, P., de Magalhães, J. P., & Plagge, A.
Affiliations
University of Liverpool (GB)
Corresponding author
Plagge, Antonius
ORCID
Venue
Molecular Brain
Publisher
Springer Science and Business Media LLC
Published
2016-04-14
Volume
9
Issue
1
Pages
39-39
ISSN
1756-6606 (ISSN-L)
DOI
10.1186/s13041-016-0219-1
PMC
PMC4832494
OpenAlex
W2336930191
Cited by
11
References
1
Citations by year
2026: 1 · 2023: 4 · 2020: 3 · 2019: 2 · 2017: 1
FWCI
0.64
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Brain (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders
  • Biotechnology and Biological Sciences Research Council (BBD5265291)
  • Wellcome Trust (102378/Z/13/Z, 099795/Z/12/Z)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
GNAS locus, Gs protein, hypothalamus, glial fibrillary acidic protein, astrocytes, ependymal layer, hypermetabolism, malnutrition, postnatal growth retardation, gliosis, leptin deficiency, vimentin, nestin
MeSH terms
Aging, Animals, Animals, Newborn, Astrocytes, Cell Count, Chromogranins, Female, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Hypothalamus, Neuroglia, RNA, Messenger, Suprachiasmatic Nucleus, Thinness, GTP-Binding Protein alpha Subunits, Gs, Gene Expression Profiling, Mice, Genetic Loci, Ependymoglial Cells, Nestin

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