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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

Schematic summary of SST, mGRF, GH, and IGF-1 expression in the En2−/− neuroendocrine axis. Red and blue arrows, respectively, indicate up- and down-regulations observed in En2−/− mice as compared to WT controls. Double-arrowed gray lines indicate comparable levels between WT and En2−/− mice. Increased levels of GH and IGF-1 mRNA, respectively observed in En2−/− pituitary and liver, are not paralleled by higher levels of circulating hormones, suggesting that a complex post-translational control of GH and IGF-1 synthesis takes place in mutant mice. GH mRNA and protein levels are instead significantly down-regulated in En2−/− hippocampus. Arrowed red lines connecting different organs indicate the action of circulating hormones onto their target tissues. The mouse brain sagittal section is a Nissl stain taken from the Allen Mouse Brain Atlas (see text footnote 2). Abbreviations are as in the text.
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Figure 6: Schematic summary of SST, mGRF, GH, and IGF-1 expression in the En2−/− neuroendocrine axis. Red and blue arrows, respectively, indicate up- and down-regulations observed in En2−/− mice as compared to WT controls. Double-arrowed gray lines indicate comparable levels between WT and En2−/− mice. Increased levels of GH and IGF-1 mRNA, respectively observed in En2−/− pituitary and liver, are not paralleled by higher levels of circulating hormones, suggesting that a complex post-translational control of GH and IGF-1 synthesis takes place in mutant mice. GH mRNA and protein levels are instead significantly down-regulated in En2−/− hippocampus. Arrowed red lines connecting different organs indicate the action of circulating hormones onto their target tissues. The mouse brain sagittal section is a Nissl stain taken from the Allen Mouse Brain Atlas (see text footnote 2). Abbreviations are as in the text.

Mentions: Our results, schematically summarized in Figure 6, indicate that regulatory mechanisms controlling GH and IGF-1 mRNA expression in the neuroendocrine system are altered in En2−/− mice. The presence of En2 mRNA in the hypothalamus–pituitary–liver axis (Figure 1) and that of an En2 binding site in the promoters of GH, IGF-1, and other genes of the pathway (Table 2) suggest that En2 might directly contribute to their transcriptional control. Indeed, recent studies revealed an unprecedented interaction between En2 and IGF-1 signaling. In the absence of En2, IGF-1 has a stronger mitogenic effect on cerebellar GNPs, due the increased activity of downstream effectors of IGF-1 signaling, such as S6 kinase (29). Thus, En2 appears to negatively regulate IGF-1 signaling during postnatal cerebellar development. Our results strengthen this link between En2 and IGF-1 signaling, and suggest that a direct transcriptional control of En2 onto genes belonging to the IGF-1 pathway takes place also in the brain–pituitary–liver axis.


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)

Schematic summary of SST, mGRF, GH, and IGF-1 expression in the En2−/− neuroendocrine axis. Red and blue arrows, respectively, indicate up- and down-regulations observed in En2−/− mice as compared to WT controls. Double-arrowed gray lines indicate comparable levels between WT and En2−/− mice. Increased levels of GH and IGF-1 mRNA, respectively observed in En2−/− pituitary and liver, are not paralleled by higher levels of circulating hormones, suggesting that a complex post-translational control of GH and IGF-1 synthesis takes place in mutant mice. GH mRNA and protein levels are instead significantly down-regulated in En2−/− hippocampus. Arrowed red lines connecting different organs indicate the action of circulating hormones onto their target tissues. The mouse brain sagittal section is a Nissl stain taken from the Allen Mouse Brain Atlas (see text footnote 2). Abbreviations are as in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Schematic summary of SST, mGRF, GH, and IGF-1 expression in the En2−/− neuroendocrine axis. Red and blue arrows, respectively, indicate up- and down-regulations observed in En2−/− mice as compared to WT controls. Double-arrowed gray lines indicate comparable levels between WT and En2−/− mice. Increased levels of GH and IGF-1 mRNA, respectively observed in En2−/− pituitary and liver, are not paralleled by higher levels of circulating hormones, suggesting that a complex post-translational control of GH and IGF-1 synthesis takes place in mutant mice. GH mRNA and protein levels are instead significantly down-regulated in En2−/− hippocampus. Arrowed red lines connecting different organs indicate the action of circulating hormones onto their target tissues. The mouse brain sagittal section is a Nissl stain taken from the Allen Mouse Brain Atlas (see text footnote 2). Abbreviations are as in the text.
Mentions: Our results, schematically summarized in Figure 6, indicate that regulatory mechanisms controlling GH and IGF-1 mRNA expression in the neuroendocrine system are altered in En2−/− mice. The presence of En2 mRNA in the hypothalamus–pituitary–liver axis (Figure 1) and that of an En2 binding site in the promoters of GH, IGF-1, and other genes of the pathway (Table 2) suggest that En2 might directly contribute to their transcriptional control. Indeed, recent studies revealed an unprecedented interaction between En2 and IGF-1 signaling. In the absence of En2, IGF-1 has a stronger mitogenic effect on cerebellar GNPs, due the increased activity of downstream effectors of IGF-1 signaling, such as S6 kinase (29). Thus, En2 appears to negatively regulate IGF-1 signaling during postnatal cerebellar development. Our results strengthen this link between En2 and IGF-1 signaling, and suggest that a direct transcriptional control of En2 onto genes belonging to the IGF-1 pathway takes place also in the brain–pituitary–liver axis.

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