The central fibroblast growth factor receptor/beta klotho system: Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform

Karin Hultman, Jarrad M. Scarlett, Arian F. Baquero, Anda Cornea, Yu Zhang, Casper B.G. Salinas, Jenny Brown, Gregory J. Morton, Erin J. Whalen, Kevin L. Grove, Frank H. Koegler, Michael W. Schwartz, Aaron J. Mercer

    Research output: Contribution to journalArticle

    1 Scopus citations

    Abstract

    Central activation of fibroblast growth factor (FGF) receptors regulates peripheral glucose homeostasis and reduces food intake in preclinical models of obesity and diabetes. The current work was undertaken to advance our understanding of the receptor expression, as sites of ligand action by FGF19, FGF21, and FGF1 in the mammalian brain remains unresolved. Recent advances in automated RNAscope in situ hybridization and droplet digital PCR (ddPCR) technology allowed us to interrogate central FGFR/beta klotho (Klb) system at the cellular level in the mouse, with relevant comparisons to nonhuman primate and human brain. FGFR1-3 gene expression was broadly distributed throughout the CNS in Mus musculus, with FGFR1 exhibiting the greatest heterogeneity. FGFR4 expression localized only in the medial habenula and subcommissural organ of mice. Likewise, Klb mRNA was restricted to the suprachiasmatic nucleus (SCh) and select midbrain and hindbrain nuclei. ddPCR in the rodent hypothalamus confirmed that, although expression levels are indeed low for Klb, there is nonetheless a bonafide subpopulation of Klb+ cells in the hypothalamus. In NHP and human midbrain and hindbrain, Klb + cells are quite rare, as is expression of FGFR4. Collectively, these data provide the most robust central map of the FGFR/Klb system to date and highlight central regions that may be of critical importance to assess central ligand effects with pharmacological dosing, such as the putative interactions between the endocrine FGFs and FGFR1/Klb, or FGF19 with FGFR4.

    Original languageEnglish (US)
    Pages (from-to)2069-2085
    Number of pages17
    JournalJournal of Comparative Neurology
    Volume527
    Issue number12
    DOIs
    StatePublished - Aug 15 2019

    Keywords

    • RRID: AB_2109645
    • RRID: AB_2532109
    • RRID: AB_839504
    • beta-klotho
    • fibroblast growth factors
    • in situ hybridization
    • obesity
    • type 2 diabetes

    ASJC Scopus subject areas

    • Neuroscience(all)

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  • Cite this

    Hultman, K., Scarlett, J. M., Baquero, A. F., Cornea, A., Zhang, Y., Salinas, C. B. G., Brown, J., Morton, G. J., Whalen, E. J., Grove, K. L., Koegler, F. H., Schwartz, M. W., & Mercer, A. J. (2019). The central fibroblast growth factor receptor/beta klotho system: Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform. Journal of Comparative Neurology, 527(12), 2069-2085. https://doi.org/10.1002/cne.24668