Fibroblast growth factor signaling in the developing neuroendocrine hypothalamus

Abstract

Fibroblast growth factor (FGF) signaling is pivotal to the formation of numerous central regions. Increasing evidence suggests FGF signaling also directs the development of the neuroendocrine hypothalamus, a collection of neuroendocrine neurons originating primarily within the nose and the ventricular zone of the diencephalon. This review outlines evidence for a role of FGF signaling in the prenatal and postnatal development of several hypothalamic neuroendocrine systems. The emphasis is placed on the nasally derived gonadotropin-releasing hormone neurons, which depend on neurotrophic cues from FGF signaling throughout the neurons' lifetime. Although less is known about neuroendocrine neurons derived from the diencephalon, recent studies suggest they also exhibit variable levels of dependence on FGF signaling. Overall, FGF signaling provides a broad spectrum of cues that ranges from genesis, cell survival/death, migration, morphological changes, to hormone synthesis in the neuroendocrine hypothalamus. Abnormal FGF signaling will deleteriously impact multiple hypothalamic neuroendocrine systems, resulting in the disruption of diverse physiological functions.

Fig. 1

Schematic representation of FGF signaling in vertebrates. In mice and humans, there are 22 FGF ligands, including secreted FGFs (FGF-s; blue spheres) and intracellular FGFs (FGF-i; brown spheres). Homology between FGFs is based on the presence of a highly conserved ~120 amino acid (aa) core region and the 30–60% overall amino acid identity across all FGFs (see inset). Secreted FGFs bind to one of the four classical FGFRs. The extracellular region of the full-length FGFR is characterized by the presence of three immunoglobulin (Ig)-like domains within which the FGF- and heparin sulfate proteoglycan (HSPG)-binding sites are localized. Stable binding of secreted FGFs in the presence of HSPG causes dimerization of FGFRs and phosphorylation of cytoplasmic tyrosine residues in the tyrosine kinase (Tk) domains, which in turn initiates a myriad of intracellular signal transduction pathways. Intracellular FGFs do not bind to the classical FGFR. Instead, they alter cellular physiology by interacting with proteins such as MAP kinase-scaffold protein (MAPK-SP) and voltage-gated sodium channel.

Fig. 2

Spatial distribution of 5 Fgf transcripts in the murine olfactory placode at E10.5, a period consistent with GnRH neuron fate specification. The image represents the coronal view from the anterior tip of the developing nasal prominence. Each Fgf transcript is represented by a different color. CP, commissural plate; NP, nasal pit. Asterisks denote the location of the presumptive ventro-medial secondary recess, where GnRH neurons emerge. The drawing is based on a previously published study [7].

Fig. 3

Representative photomicrographs of neurons immunoreactive for mature GnRH in 100-day-old (A, B) and 550-day-old (C, D) wildtype (WT; A, C), and homozygous dnFGFR mice (B, D) at the plane of the organum vasculosum of lamina terminalis, the area of greatest GnRH neuron concentration. Note the significant reduction in the number of GnRH neurons (brown staining) in 550-day old dnFGFR mice compared to the younger dnFGFR mice, and absence of such an age-dependent reduction in the WT mice. Scale bar = 100 μm.

Fig. 4

Representative photomicrographs of neurons immunoreactive for mature OT (A-D) and AVP (E-H) in a newborn wildtype (WT; A, C, E, G) and homozygous Fgf8 hypomorph (HOMO; B, D, F, H) in the PVN, SON and SCN. Note the visual reduction of OT and AVP neurons in WT compared to Fgf8 hypomorph in the PVN (A, B, E, F), SON (C, D) and SCN (G, H). The reduction is more severe in the SON and SCN of the Fgf8 hypomorph, with essentially no immunoreactive neurons remaining. Brown color represents specific immunostaining. Green color represents methyl green nuclear counterstain. The boundary of SON is delineated by the dotted line. Inset in C is a low-magnification photomicrograph of the same section, with the SON delineated by the dotted line. Arrow points to the third ventricle. Scale bar = 100 μm.