Fibroblast growth factor receptor signaling affects development and function of dopamine neurons – inhibition results in a schizophrenia‐like syndrome in transgenic mice

Abstract

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

“…nFGFR1, CBP, and Nurr1 accumulate in the nuclei of developing DA progenitors, all three proteins colocalizing in the nuclear bodies (Fang et al, 2005; Baron et al, 2012). The knock down of Nurr1 or the blocking of endogenous FGFR1 in DA progenitors attenuates neuronal development in transgenic mice, thus verifying their ontogenic function (Klejbor et al, 2006; Smidt and Burbach, 2009). nFGFR1 directly targets the Patch2, Ngn, RAR, and Nurr1 genes (Terranova et al, 2015), which are instrumental in DA neuronal development, and nFGFR1, together with Nurr1, binds and co‐activates the TH gene involved in DA synthesis (Lee et al, 2012).…”

“…Development of these neurons is controlled by nFGFR1 and its nuclear partner proteins (Klejbor et al, 2006; Smidt and Burbach, 2009). nFGFR1, CBP, and Nurr1 accumulate in the nuclei of developing DA progenitors, all three proteins colocalizing in the nuclear bodies (Fang et al, 2005; Baron et al, 2012).…”

Unilateral 6-OHDA <i>th-fgfr1</i>(<i>tk-</i>) mouse model supports the role of FGFs in Parkinson’s disease and the effects of nicotine and L-DOPA on spontaneous motor impairments

“…Phenotypically, th-fgfr1(tk-) mice have smaller and lessdense midbrain DA neurons, resembling the DA neuronal hypoplasia observed in adult PD patients [38,39]. These mice display behavioral abnormalities associated with dysfunctional DA release such as impaired sensorimotor gating (reduced prepulse inhibition of the startle response), abnormal social interaction and cognitive dysfunction [37,40,41]. …”

“…To further assess the role of substantia nigra (SN)-expressed FGFs and its homologues in PD, a transgenic mouse model expressing fgfr1(tk-) receptor from the tyrosine hydroxylase gene promoter was generated [37]. Phenotypically, th-fgfr1(tk-) mice have smaller and lessdense midbrain DA neurons, resembling the DA neuronal hypoplasia observed in adult PD patients [38,39].…”

“…Mice homozygous for th-fgfr1(tk-) transgene and control mice (transgene free) lines were derived from the same parental BCF1 (C57BL/10J/C3H/HeJ) mouse strain. The lines showed stable behavioral differences in all generations investigated [37]. Mice used in all specific experiments were selected from multiple litters.…”