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 Grove, Frank H. Koegler, Michael W. Schwartz, Aaron J. Mercer

Research output: Contribution to journalArticle

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)
JournalJournal of Comparative Neurology
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Fibroblast Growth Factor Receptors
Primates
In Situ Hybridization
Rhombencephalon
Mesencephalon
Hypothalamus
Subcommissural Organ
Habenula
Ligands
Fibroblast Growth Factor 1
Polymerase Chain Reaction
Suprachiasmatic Nucleus
Brain
Rodentia
Homeostasis
Obesity
Eating
Pharmacology
Technology
Gene Expression

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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

In: Journal of Comparative Neurology, 01.01.2019.

Research output: Contribution to journalArticle

Hultman, Karin ; Scarlett, Jarrad M. ; Baquero, Arian F. ; Cornea, Anda ; Zhang, Yu ; Salinas, Casper B.G. ; Brown, Jenny ; Morton, Gregory J. ; Whalen, Erin J. ; Grove, Kevin ; Koegler, Frank H. ; Schwartz, Michael W. ; Mercer, Aaron J. / 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. In: Journal of Comparative Neurology. 2019.
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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.",
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AU - Hultman, Karin

AU - Scarlett, Jarrad M.

AU - Baquero, Arian F.

AU - Cornea, Anda

AU - Zhang, Yu

AU - Salinas, Casper B.G.

AU - Brown, Jenny

AU - Morton, Gregory J.

AU - Whalen, Erin J.

AU - Grove, Kevin

AU - Koegler, Frank H.

AU - Schwartz, Michael W.

AU - Mercer, Aaron J.

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N2 - 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.

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KW - RRID: AB_839504

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