PMC:2944667 / 14082-21195
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2944667","sourcedb":"PMC","sourceid":"2944667","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2944667","text":"FGFs and the developing dorsal telencephalon\nAn essential feature of secreted morphogens during development is their ability to regulate the neurogenic process in a spatially restricted manner. Two distinct areas of the dorsal telencephalon are of relevance to the pathophysiology of neuropsychiatric disorders, the cerebral cortex and the hippocampus, the first developing primarily prenatally, and the second both prenatally and postnatally. In this section we will focus more on the prenatal role of FGF receptors on cortical development. Later sections will discuss the role of FGF on hippocampal development and relate these phenomena to neuropsychiatric disorders.\nFGF8, FGF17 and FGF18 are expressed in the anterior telencephalon (Figure 2), and evidence suggests that this high rostral and low caudal gradient of FGF signaling contributes to prefrontal cortex (PFC) development (Fukuchi-Shimogori and Grove, 2001; Cholfin and Rubenstein, 2007). A given amount of FGFs in the developing cortical field can determine whether stem cells will form specific sub-regions such as somatosensory cortex or PFC (Fukuchi-Shimogori and Grove, 2001). Alterations in the level of FGFs have been shown to lead to abnormal behaviors in animals (Scearce-Levie et al., 2008). FGF8 is negatively regulated by BMP (Crossley et al., 2001; Ohkubo et al., 2002) and in turn, FGF8 restricts WNT3a expression, confining it into the hem region (Shimogori et al., 2004). WNT3a expression in posterior hem regions is important for the formation of the hippocampus (Lee et al., 2000).\nIf we consider the secreted signaling molecules expressed by NSCs in the cortical primordium, only disruptions in the FGF pathways have thus far resulted in major defects in cortical development (Hebert et al., 2003; Cheng et al., 2006). Although overexpression of a stabilized β-catenin, which is downstream of the WNT pathway, increases cortical size (Chenn and Walsh, 2002), the disruption of the WNT pathway affects the hippocampus rather than the cortex (Galceran et al., 2000). Thus, normal embryonic cortical development primarily depends on FGF signaling, and in order to better understand the mechanisms mediating these roles, several FGF receptor mutant models have been generated.\nMice that transiently overexpress a dominant negative fgfr1 gene that interferes with normal functioning of all receptor types during early embryogenesis have a smaller cortex, particularly in the frontal and temporal regions, and reduced numbers of excitatory neurons (Shin et al., 2004). Furthermore, these mice exhibited hyperactivity. Specific receptor knockouts have subsequently shown the relative contribution of each FGF receptor to cortical development. In order to avoid embryonic lethality of fgfr1 and fgfr2 systemic gene knockouts, fgfr alleles containing loxP site have been recombined in vivo with a variety of Cre lines, including the foxg1 knock-in Cre, nestin-Cre and hgfap-Cre lines. Mice lacking fgfr1 in radial glial progenitors driven by hgfap-Cre (which targets the dorsal telencephalon and hippocampal anlage), exhibited severe reduction of hippocampal volume, almost complete absence of midline telencephalic commissures due to abnormal development of midline glia, and decreased inhibitory interneuron number in the cortex and hippocampus (Ohkubo et al., 2004; Smith et al., 2006; Muller Smith et al., 2008). In contrast, the number of cortical excitatory neurons was not decreased in mice lacking fgfr1 alone (Muller Smith et al., 2008). However, mice lacking fgfr2 alone or in combination with fgfr1, via hgfap-Cre mediated recombination, showed a decrease in cortical excitatory neurons and volume, both of which were more pronounced in the medial prefrontal area of the cortex (Stevens et al., 2010). The mechanism of these abnormalities leading to a loss of cortical excitatory neurons resides in the ability of FGFR2 signaling to induce radial glial stem cells to re-enter the cell cycle, particularly in anterior regions. Therefore, FGFR2 support prefrontal cortical development by promoting the self-renewal or maintenance of cortical stem cells. These data converge with previous work demonstrating that PFC size is reduced by knockout of FGF17, a ligand for FGFR2 (Cholfin and Rubenstein, 2008).\nConsistent with the decreased number of excitatory projection neurons in PFC in conditional knockouts for fgfr2 driven by the hgfap-Cre transgene, glutamatergic synapses in the bed nuclei of the stria terminalis (BST), an area that receives projections from the PFC and in turn projects to the hypothalamus, were also reduced in these mice. A decreased number of GABAergic neurons in the BST was also noted in these animals, which is likely to be secondary to decreased glutamate input, as FGFR2 was not targeted in this region (Stevens et al., 2010). These changes may have important consequences for the correct functioning of limbic circuitry.\nMice constitutively lacking FGFR3 through the germline have skeletal defects but have not been reported to have abnormal cortical morphogenesis. (Colvin et al., 1996; Oh et al., 2003). On the other hand, mice with activating mutations of fgfr3 have an increase in the rate of the cell cycle of cortical stem cells in early neurogenesis and an increase in the generation of TBR2+ IPCs at later stages, leading to increased cortical size and cortical cell number (Inglis-Broadgate et al., 2005; Thomson et al., 2007, 2009). The caudal and lateral areas of the cortex were most affected, reflecting the natural gradient of fgfr3 expression. Thus, FGFR2 and FGFR3 both appear to influence the appropriate proliferation of stem cells in different regions of cortex (anterior and posterior, respectively), suggesting that the regulation of signaling by each of these receptors individually and in combination may be critical for the appropriate expansion of different cortical areas. Compound mutation for fgfr1, fgfr2 and fgfr3 in the early anterior neural tube (driven by foxg1-Cre) results in an almost complete agenesis of both dorsal and ventral telencephalic regions (Gutin et al., 2006; Hebert and Fishell, 2008).\nThe downstream targets that mediate FGF regulated cellular events are still under investigation. Relevant to the early patterning processes in the cortex, FGF8-mediated activation of FGFRs is known to repress genes that specify dorsal and posterior cell fate including coup-tf1, emx2, and wnt8b (Crossley et al., 2001; Garel et al., 2003; Storm et al., 2006). FGF and other signaling factors also induce RAS/MAPK pathways, supporting NSC proliferation and self-renewal, and PI3K/AKT pathways, supporting cell survival. Several transcription factor genes are also activated by FGF signaling in NSCs as well as neuronal progeny, including pea3, erm (etv5), and er81 (etv1) some of which are anteriorly expressed (Hasegawa et al., 2004; Cholfin and Rubenstein, 2008) and may be involved in cell differentiation or fate. The multiplicity of targets demonstrates how master regulatory factors such as FGF may exert multifaceted roles in stem cells and their 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