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Fibroblast growth factor 8 regulates postnatal development of paraventricular nucleus neuroendocrine cells.

Rodriguez KM, Stevenson EL, Stewart CE, Linscott ML, Chung WC - Behav Brain Funct (2015)

Bottom Line: Fibroblast growth factors (FGFs) are crucial signaling molecules that direct the development of the vertebrate brain.FGF8 gene signaling in particular, may be important for the development of the hypothalamus-pituitary-adrenal (HPA)-axis.Indeed, newborn Fgf8 hypomorphic mice harbor a major reduction in the number of vasopressin (VP) neurons in the paraventricular nucleus (PVN), the central output component of the HPA-axis.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA. krodri10@kent.edu.

ABSTRACT

Background: Fibroblast growth factors (FGFs) are crucial signaling molecules that direct the development of the vertebrate brain. FGF8 gene signaling in particular, may be important for the development of the hypothalamus-pituitary-adrenal (HPA)-axis. Indeed, newborn Fgf8 hypomorphic mice harbor a major reduction in the number of vasopressin (VP) neurons in the paraventricular nucleus (PVN), the central output component of the HPA-axis. Additionally, recent studies indicated that adult heterozygous ((+/neo)) Fgf8 hypomorphic mice exhibit more anxiety-like behaviors than wildtype (WT) mice. These studies led us to investigate whether Fgf8 hypomorphy abrogated VP and/or corticotropin-releasing hormone (CRH) neuronal development in the postnatal day (PN) 21 and adult mouse PVN. Furthermore, we studied whether Fgf8 hypomorphy disrupted HPA responsiveness in these mice.

Methods: Using immunohistochemistry, we examined the development of VP and CRH neurons located in the PVN of PN 21 and adult Fgf8 (+/neo) mice. Moreover, we used a restraint stress (RS) paradigm and measured corticosterone levels with enzyme immunoassays in order to assess HPA axis activation.

Results: The number of VP neurons in the PVN did not differ between WT and Fgf8 (+/neo) mice on PN 21 and in adulthood. In contrast, CRH immunoreactivity was much higher in Fgf8 (+/neo) mice than in WT mice on PN 21, this difference was no longer shown in adult mice. RS caused a higher increase in corticosterone levels in adult Fgf8 (+/neo) mice than in WT mice after 15 min, but no difference was seen after 45 min.

Conclusions: First, Fgf8 hypomorphy did not eliminate VP and CRH neurons in the mouse PVN, but rather disrupted the postnatal timing of neuropeptide expression onset in PVN neurons. Second, Fgf8 hypomorphy may, in part, be an explanation for affective disorders involving hyperactivity of the HPA axis, such as anxiety.

No MeSH data available.


Related in: MedlinePlus

Bar graphs depicting corticosterone levels in adult WT and Fgf8+/neo mice in response to RS for a 15 or b 45 min. a RS for 15 min caused a significant rise in corticosteroid levels in WT (13.8 ± 0.8 μg/dL) and Fgf8+/neo mice (17.8 ± 1.3 sem μg/dL) compared to NS WT (0.8 ± 0.4 sem μg/dL) and Fgf8+/neo mice (0.6 ± 0.3 sem μg/dL). The rise in corticosteroid levels after 15 min of RS was significantly lower in WT than in Fgf8+/neo mice. Differences in letters indicate p < 0.05. b RS for 45 min caused a significant rise in corticosteroid levels in WT (40.0 ± 2.5 μg/dL) and Fgf8+/neo mice (47.7 ± 16.1 sem μg/dL) compared to NS WT (2.0 ± 1.4 sem μg/dL) and Fgf8+/neo mice (1.9 ± 0.7 sem μg/dL). The rise in corticosteroid levels after 45 min of RS did not differ between WT and Fgf8+/neo mice. Asterisk indicates p < 0.05 between animals treated with NS or RS conditions
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Fig3: Bar graphs depicting corticosterone levels in adult WT and Fgf8+/neo mice in response to RS for a 15 or b 45 min. a RS for 15 min caused a significant rise in corticosteroid levels in WT (13.8 ± 0.8 μg/dL) and Fgf8+/neo mice (17.8 ± 1.3 sem μg/dL) compared to NS WT (0.8 ± 0.4 sem μg/dL) and Fgf8+/neo mice (0.6 ± 0.3 sem μg/dL). The rise in corticosteroid levels after 15 min of RS was significantly lower in WT than in Fgf8+/neo mice. Differences in letters indicate p < 0.05. b RS for 45 min caused a significant rise in corticosteroid levels in WT (40.0 ± 2.5 μg/dL) and Fgf8+/neo mice (47.7 ± 16.1 sem μg/dL) compared to NS WT (2.0 ± 1.4 sem μg/dL) and Fgf8+/neo mice (1.9 ± 0.7 sem μg/dL). The rise in corticosteroid levels after 45 min of RS did not differ between WT and Fgf8+/neo mice. Asterisk indicates p < 0.05 between animals treated with NS or RS conditions

Mentions: Fifteen minutes. Two-way analysis of variance showed that RS for 15 min caused a significant increase in circulating corticosterone levels in adult WT and Fgf8+/neo mice (Df = 19, F = 364.5, p < 0.001). Moreover, there was a significant main genotype effect (Df = 19, F = 5.5, p < 0.05), and interaction between restraint and genotype (Df = 19, F = 6.8, p < 0.05). Student t test analysis showed that the level of corticosterone was much higher in RS than NS WT and Fgf8+/neo mice (p < 0.001). Furthermore, elevation of circulating corticosterone levels after RS was higher in Fgf8+/neo mice than in WT mice (p < 0.003) (Fig. 3a).Fig. 3


Fibroblast growth factor 8 regulates postnatal development of paraventricular nucleus neuroendocrine cells.

Rodriguez KM, Stevenson EL, Stewart CE, Linscott ML, Chung WC - Behav Brain Funct (2015)

Bar graphs depicting corticosterone levels in adult WT and Fgf8+/neo mice in response to RS for a 15 or b 45 min. a RS for 15 min caused a significant rise in corticosteroid levels in WT (13.8 ± 0.8 μg/dL) and Fgf8+/neo mice (17.8 ± 1.3 sem μg/dL) compared to NS WT (0.8 ± 0.4 sem μg/dL) and Fgf8+/neo mice (0.6 ± 0.3 sem μg/dL). The rise in corticosteroid levels after 15 min of RS was significantly lower in WT than in Fgf8+/neo mice. Differences in letters indicate p < 0.05. b RS for 45 min caused a significant rise in corticosteroid levels in WT (40.0 ± 2.5 μg/dL) and Fgf8+/neo mice (47.7 ± 16.1 sem μg/dL) compared to NS WT (2.0 ± 1.4 sem μg/dL) and Fgf8+/neo mice (1.9 ± 0.7 sem μg/dL). The rise in corticosteroid levels after 45 min of RS did not differ between WT and Fgf8+/neo mice. Asterisk indicates p < 0.05 between animals treated with NS or RS conditions
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4634727&req=5

Fig3: Bar graphs depicting corticosterone levels in adult WT and Fgf8+/neo mice in response to RS for a 15 or b 45 min. a RS for 15 min caused a significant rise in corticosteroid levels in WT (13.8 ± 0.8 μg/dL) and Fgf8+/neo mice (17.8 ± 1.3 sem μg/dL) compared to NS WT (0.8 ± 0.4 sem μg/dL) and Fgf8+/neo mice (0.6 ± 0.3 sem μg/dL). The rise in corticosteroid levels after 15 min of RS was significantly lower in WT than in Fgf8+/neo mice. Differences in letters indicate p < 0.05. b RS for 45 min caused a significant rise in corticosteroid levels in WT (40.0 ± 2.5 μg/dL) and Fgf8+/neo mice (47.7 ± 16.1 sem μg/dL) compared to NS WT (2.0 ± 1.4 sem μg/dL) and Fgf8+/neo mice (1.9 ± 0.7 sem μg/dL). The rise in corticosteroid levels after 45 min of RS did not differ between WT and Fgf8+/neo mice. Asterisk indicates p < 0.05 between animals treated with NS or RS conditions
Mentions: Fifteen minutes. Two-way analysis of variance showed that RS for 15 min caused a significant increase in circulating corticosterone levels in adult WT and Fgf8+/neo mice (Df = 19, F = 364.5, p < 0.001). Moreover, there was a significant main genotype effect (Df = 19, F = 5.5, p < 0.05), and interaction between restraint and genotype (Df = 19, F = 6.8, p < 0.05). Student t test analysis showed that the level of corticosterone was much higher in RS than NS WT and Fgf8+/neo mice (p < 0.001). Furthermore, elevation of circulating corticosterone levels after RS was higher in Fgf8+/neo mice than in WT mice (p < 0.003) (Fig. 3a).Fig. 3

Bottom Line: Fibroblast growth factors (FGFs) are crucial signaling molecules that direct the development of the vertebrate brain.FGF8 gene signaling in particular, may be important for the development of the hypothalamus-pituitary-adrenal (HPA)-axis.Indeed, newborn Fgf8 hypomorphic mice harbor a major reduction in the number of vasopressin (VP) neurons in the paraventricular nucleus (PVN), the central output component of the HPA-axis.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA. krodri10@kent.edu.

ABSTRACT

Background: Fibroblast growth factors (FGFs) are crucial signaling molecules that direct the development of the vertebrate brain. FGF8 gene signaling in particular, may be important for the development of the hypothalamus-pituitary-adrenal (HPA)-axis. Indeed, newborn Fgf8 hypomorphic mice harbor a major reduction in the number of vasopressin (VP) neurons in the paraventricular nucleus (PVN), the central output component of the HPA-axis. Additionally, recent studies indicated that adult heterozygous ((+/neo)) Fgf8 hypomorphic mice exhibit more anxiety-like behaviors than wildtype (WT) mice. These studies led us to investigate whether Fgf8 hypomorphy abrogated VP and/or corticotropin-releasing hormone (CRH) neuronal development in the postnatal day (PN) 21 and adult mouse PVN. Furthermore, we studied whether Fgf8 hypomorphy disrupted HPA responsiveness in these mice.

Methods: Using immunohistochemistry, we examined the development of VP and CRH neurons located in the PVN of PN 21 and adult Fgf8 (+/neo) mice. Moreover, we used a restraint stress (RS) paradigm and measured corticosterone levels with enzyme immunoassays in order to assess HPA axis activation.

Results: The number of VP neurons in the PVN did not differ between WT and Fgf8 (+/neo) mice on PN 21 and in adulthood. In contrast, CRH immunoreactivity was much higher in Fgf8 (+/neo) mice than in WT mice on PN 21, this difference was no longer shown in adult mice. RS caused a higher increase in corticosterone levels in adult Fgf8 (+/neo) mice than in WT mice after 15 min, but no difference was seen after 45 min.

Conclusions: First, Fgf8 hypomorphy did not eliminate VP and CRH neurons in the mouse PVN, but rather disrupted the postnatal timing of neuropeptide expression onset in PVN neurons. Second, Fgf8 hypomorphy may, in part, be an explanation for affective disorders involving hyperactivity of the HPA axis, such as anxiety.

No MeSH data available.


Related in: MedlinePlus