Abstract

Secreted proteins of the fibroblast growth factor (FGF) family play important roles during development of various organ systems. A detailed knowledge of their temporal and spatial expression profiles, especially of closely related FGF family members, are essential to further identification of specific functions in distinct tissues. In the central nervous system dopaminergic neurons of the substantia nigra and their axonal projections into the striatum progressively degenerate in Parkinson's disease. In contrast, FGF-2 deficient mice display increased numbers of dopaminergic neurons. In this study, we determined the expression profiles of all 22 FGF-ligands and 10 FGF-receptor isoforms, in order to clarify, if FGF-2 deficiency leads to compensatory up-regulation of other FGFs in the nigrostriatal system. Three tissues, ventral mesencephalon (VM), striatum (STR) and as reference tissue spinal cord (SC) of wild-type and FGF-2 deficient mice at four developmental stages E14.5, P0, P28, and adult were comparatively analyzed by quantitative RT-PCR. As no differences between the genotypes were observed, a compensatory up-regulation can be excluded. Moreover, this analysis revealed that the majority of FGF-ligands (18/22) and FGF-receptors (9/10) are expressed during normal development of the nigrostriatal system and identified dynamic changes for some family members. By comparing relative expression level changes to SC reference tissue, general alterations in all 3 tissues, such as increased expression of FGF-1, -2, -22, FgfR-2c, -3c and decreased expression of FGF-13 during postnatal development were identified. Further, specific changes affecting only one tissue, such as increased FGF-16 (STR) or decreased FGF-17 (VM) expression, or two tissues, such as decreased expression of FGF-8 (VM, STR) and FGF-15 (SC, VM) were found. Moreover, 3 developmentally down-regulated FGFs (FGF-8b, FGF-15, FGF-17a) were functionally characterized by plasmid-based over-expression in dissociated E11.5 VM cell cultures, however, such a continuous exposure had no influence on the yield of dopaminergic neurons in vitro.

Highlights

  • Fibroblast growth factor 2 (FGF-2) is a member of the fibroblast growth factor (FGF) family, which comprises small proteins of about 150–300 amino acids length with a common conserved core domain [1]

  • Exceptions included FGF-6, FGF-21 and FGF-23, which were not detected in any tissue analyzed, and FGF-4 and b-Klotho, which were absent in most tissues except of low levels of FGF-4 (DCT = 14.8) and b-Klotho (DCT = 13.5) in adult spinal cord (SC) and P28 SC, respectively

  • To allow a better comparison of the expression profiles of individual genes, expression levels were normalized to P0 SC, which was set to 1

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Summary

Introduction

Fibroblast growth factor 2 (FGF-2) is a member of the FGF family, which comprises small proteins of about 150–300 amino acids length with a common conserved core domain [1]. FGF-2 has physiological relevance for dopaminergic (DA) neurons of the nigrostriatal system [16] and FGF-2 depletion might be related to Parkinson’s disease [17]. Based on their mode of action, the 22 mammalian FGFs have been classified into intracrine, canonical and hormone-like FGFs [1,18,19]. Canonical FGFs are secreted proteins, which function in an autocrine/paracrine manner. They form ternary complexes with heparan sulfates and extracellular domains of transmembrane FGF-receptors (FgfRs). Hormone-like FGFs possess a much lower binding affinity to FgfRs and heparan sulfates compared to canonical FGFs, which is balanced upon binding of the respective co-receptors a-Klotho or b-Klotho [19]

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