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GH Dysfunction in Engrailed-2 Knockout Mice, a Model for Autism Spectrum Disorders.

Provenzano G, Clementi E, Genovesi S, Scali M, Tripathi PP, Sgadò P, Bozzi Y - Front Pediatr (2014)

Bottom Line: IGF-1 levels were found increased in the blood and decreased in the cerebrospinal fluid of ASD children.IGF-1 mRNA was significantly up-regulated in the liver and down-regulated in the En2 (-/-) hippocampus, but no differences were detected in the levels of IGF-1 protein between the two genotypes.Our data strengthen the notion that altered GH levels in the hippocampus may be involved in learning disabilities associated to ASD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuropathology, Centre for Integrative Biology (CIBIO), University of Trento , Trento , Italy.

ABSTRACT
Insulin-like growth factor 1 (IGF-1) signaling promotes brain development and plasticity. Altered IGF-1 expression has been associated to autism spectrum disorders (ASD). IGF-1 levels were found increased in the blood and decreased in the cerebrospinal fluid of ASD children. Accordingly, IGF-1 treatment can rescue behavioral deficits in mouse models of ASD, and IGF-1 trials have been proposed for ASD children. IGF-1 is mainly synthesized in the liver, and its synthesis is dependent on growth hormone (GH) produced in the pituitary gland. GH also modulates cognitive functions, and altered levels of GH have been detected in ASD patients. Here, we analyzed the expression of GH, IGF-1, their receptors, and regulatory hormones in the neuroendocrine system of adult male mice lacking the homeobox transcription factor Engrailed-2 (En2 (-/-) mice). En2 (-/-) mice display ASD-like behaviors (social interactions, defective spatial learning, increased seizure susceptibility) accompanied by relevant neuropathological changes (loss of cerebellar and forebrain inhibitory neurons). Recent studies showed that En2 modulates IGF-1 activity during postnatal cerebellar development. We found that GH mRNA expression was markedly deregulated throughout the neuroendocrine axis in En2 (-/-) mice, as compared to wild-type controls. In mutant mice, GH mRNA levels were significantly increased in the pituitary gland, blood, and liver, whereas decreased levels were detected in the hippocampus. These changes were paralleled by decreased levels of GH protein in the hippocampus but not other tissues of En2 (-/-) mice. IGF-1 mRNA was significantly up-regulated in the liver and down-regulated in the En2 (-/-) hippocampus, but no differences were detected in the levels of IGF-1 protein between the two genotypes. Our data strengthen the notion that altered GH levels in the hippocampus may be involved in learning disabilities associated to ASD.

No MeSH data available.


Related in: MedlinePlus

Levels of GH and IGF-1 hormones in WT and En2−/− mice. (A,B) ELISA quantification of GH (A) and IGF-1 (B) levels in serum and hippocampal (hippo) and liver protein extracts, as indicated. Values are plotted as mean ± SEM (five animals per genotype, in duplicate; *p < 0.05, Student’s t-test, En2−/− vs. WT). Genotypes are as indicated.
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Figure 5: Levels of GH and IGF-1 hormones in WT and En2−/− mice. (A,B) ELISA quantification of GH (A) and IGF-1 (B) levels in serum and hippocampal (hippo) and liver protein extracts, as indicated. Values are plotted as mean ± SEM (five animals per genotype, in duplicate; *p < 0.05, Student’s t-test, En2−/− vs. WT). Genotypes are as indicated.

Mentions: The altered levels of GH and IGF-1 mRNA expression detected in the En2−/− neuroendocrine axis prompted us to investigate the levels of these hormones in the hippocampus, serum, and liver of both genotypes. ELISA assays revealed a significant reduction (−54%, p < 0.05) of GH protein levels in the hippocampus of En2−/− mice, as compared to WT littermates, while no difference was detected in serum samples (Figure 5A). Hippocampal, liver, and serum IGF-1 protein levels did not significantly differ between the two genotypes (Figure 5B).


GH Dysfunction in Engrailed-2 Knockout Mice, a Model for Autism Spectrum Disorders.

Provenzano G, Clementi E, Genovesi S, Scali M, Tripathi PP, Sgadò P, Bozzi Y - Front Pediatr (2014)

Levels of GH and IGF-1 hormones in WT and En2−/− mice. (A,B) ELISA quantification of GH (A) and IGF-1 (B) levels in serum and hippocampal (hippo) and liver protein extracts, as indicated. Values are plotted as mean ± SEM (five animals per genotype, in duplicate; *p < 0.05, Student’s t-test, En2−/− vs. WT). Genotypes are as indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150208&req=5

Figure 5: Levels of GH and IGF-1 hormones in WT and En2−/− mice. (A,B) ELISA quantification of GH (A) and IGF-1 (B) levels in serum and hippocampal (hippo) and liver protein extracts, as indicated. Values are plotted as mean ± SEM (five animals per genotype, in duplicate; *p < 0.05, Student’s t-test, En2−/− vs. WT). Genotypes are as indicated.
Mentions: The altered levels of GH and IGF-1 mRNA expression detected in the En2−/− neuroendocrine axis prompted us to investigate the levels of these hormones in the hippocampus, serum, and liver of both genotypes. ELISA assays revealed a significant reduction (−54%, p < 0.05) of GH protein levels in the hippocampus of En2−/− mice, as compared to WT littermates, while no difference was detected in serum samples (Figure 5A). Hippocampal, liver, and serum IGF-1 protein levels did not significantly differ between the two genotypes (Figure 5B).

Bottom Line: IGF-1 levels were found increased in the blood and decreased in the cerebrospinal fluid of ASD children.IGF-1 mRNA was significantly up-regulated in the liver and down-regulated in the En2 (-/-) hippocampus, but no differences were detected in the levels of IGF-1 protein between the two genotypes.Our data strengthen the notion that altered GH levels in the hippocampus may be involved in learning disabilities associated to ASD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuropathology, Centre for Integrative Biology (CIBIO), University of Trento , Trento , Italy.

ABSTRACT
Insulin-like growth factor 1 (IGF-1) signaling promotes brain development and plasticity. Altered IGF-1 expression has been associated to autism spectrum disorders (ASD). IGF-1 levels were found increased in the blood and decreased in the cerebrospinal fluid of ASD children. Accordingly, IGF-1 treatment can rescue behavioral deficits in mouse models of ASD, and IGF-1 trials have been proposed for ASD children. IGF-1 is mainly synthesized in the liver, and its synthesis is dependent on growth hormone (GH) produced in the pituitary gland. GH also modulates cognitive functions, and altered levels of GH have been detected in ASD patients. Here, we analyzed the expression of GH, IGF-1, their receptors, and regulatory hormones in the neuroendocrine system of adult male mice lacking the homeobox transcription factor Engrailed-2 (En2 (-/-) mice). En2 (-/-) mice display ASD-like behaviors (social interactions, defective spatial learning, increased seizure susceptibility) accompanied by relevant neuropathological changes (loss of cerebellar and forebrain inhibitory neurons). Recent studies showed that En2 modulates IGF-1 activity during postnatal cerebellar development. We found that GH mRNA expression was markedly deregulated throughout the neuroendocrine axis in En2 (-/-) mice, as compared to wild-type controls. In mutant mice, GH mRNA levels were significantly increased in the pituitary gland, blood, and liver, whereas decreased levels were detected in the hippocampus. These changes were paralleled by decreased levels of GH protein in the hippocampus but not other tissues of En2 (-/-) mice. IGF-1 mRNA was significantly up-regulated in the liver and down-regulated in the En2 (-/-) hippocampus, but no differences were detected in the levels of IGF-1 protein between the two genotypes. Our data strengthen the notion that altered GH levels in the hippocampus may be involved in learning disabilities associated to ASD.

No MeSH data available.


Related in: MedlinePlus