Dysregulation of the IGF‐I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders

Chen, Jianling; Alberts, Ian L.; Li, Xiaohong

doi:10.1016/j.ijdevneu.2014.03.006

Cited by 135 publications

(105 citation statements)

References 73 publications

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“…is an activator of the Akt-mTOR pathway (15,16) a molecular cascade involved in several neurodevelopmental disorders that is hypofunctional in CDKL5 -/y mice (11). Moreover, IGF-1 treatment was found to ameliorate spine dynamics and behavioural phenotype in murine models of RTT involving MeCP2 deletion (17,18) and a clinical trial is ongoing in MeCP2 patients (19).…”

mentioning

confidence: 99%

Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

Sala

Putignano

Chelini

et al. 2016

Biological Psychiatry

109

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Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by IGF-1, Biological Psychiatry, http: //dx.doi.org/10.1016/j.biopsych. 2015.08.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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mentioning

confidence: 99%

Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

Sala

Putignano

Chelini

et al. 2016

Biological Psychiatry

109

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“…CA-β-catenin Control mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, which is a critical RANK/ RANKL downstream signalling pathway [38][39][40]. However, the potential crosstalk between Wnt/β-catenin and other signalling pathways in osteoclastogenesis requires further studies.…”

Section: Iod/areamentioning

confidence: 99%

Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Sui

Deng

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Activation of the Wnt/β-catenin signalling pathway has been widely investigated in bone biology and shown to promote bone formation. However, its specific effects on osteoclast differentiation have not been fully elucidated. Our study aimed to identify the role of β-catenin in osteoclastogenesis and bone homeostasis. Methods: In the present study, exon 3 in the β-catenin gene (Ctnnb1) allele encoding phosphorylation target serine/threonine residues was flanked by floxP sequences. We generated mice exhibiting conditional β-catenin activation (Ctsk-Cre;Ctnnb1^{flox(exon3)/+}, designated CA-β-catenin) by crossing Ctnnb1^{flox(exon3)/flox(exon3)} mice with osteoclast-specific Ctsk-Cre mice. Bone growth and bone mass were analysed by micro-computed tomography (micro-CT) and histomorphometry. To further examine osteoclast activity, osteoclasts were induced from bone marrow monocytes (BMMs) isolated from CA-β-catenin and Control mice in vitro. Osteoclast differentiation was detected by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence staining and reverse transcription-quantitative PCR (RT–qPCR) analysis. Results: Growth retardation and low bone mass were observed in CA-β-catenin mice. Compared to controls, CA-β-catenin mice had significantly reduced trabecular bone numbers under growth plates as well as thinner cortical bones. Moreover, increased TRAP-positive osteoclasts were observed on the surfaces of trabecular bones and cortical bones in the CA-β-catenin mice; consistent results were observed in vitro. In the CA-β-catenin group, excessive numbers of osteoclasts were induced from BMMs, accompanied by the increased expression of osteoclast-associated marker genes. Conclusion: These results indicated that the constitutive activation of β-catenin in osteoclasts promotes osteoclast formation, resulting in bone loss.

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“…Increasing BDNF expression in these mice rescues TrkB/Akt signaling and breathing dysfunction [143]. Also, treatment with insulin-like growth factor 1 (IGF-1) which, like BDNF, activates the mTOR pathway [144], rescues synaptic deficits and social and anxiety behavior in MeCP2 mice and in human Rett syndrome [141,145]. Reversal of autistic behavior in these genetic models of ASD, particularly in Rett syndrome, which arises from a mutation in an epigenetic regulatory gene, supports the exciting possibility that autistic behavior can also be reversed in idiopathic autism.…”

Section: De-regulated Mtor Dendritic Spines and Synaptic Transmissionmentioning

confidence: 99%

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

Fahnestock¹

2015

Autism Open Access

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Although autism is highly genetic, "idiopathic" cases, for which there is no known genetic basis, may be due to epigenetic or environmental factors. Indeed, recent efforts have been highly successful in identifying hundreds of genes, as well as interacting epigenetic and environmental factors that contribute to autism susceptibility, corroborating the importance of gene x environment interactions in the etiology of autism. Nevertheless, a more thorough understanding of the proteins and pathways that lead from genes to behavior is desperately needed.Genetic studies have implicated molecules involved in synapse development and plasticity in autism pathogenesis. Among these are brain-derived neurotrophic factor (BDNF), its receptor, tropomyosin-related kinase B (TrkB), and their signaling pathways including mammalian target of rapamycin (mTOR), which is increased in most forms of syndromic autism. Notably, abnormalities in these molecules have also been found in idiopathic autism. Postmortem brain tissue of subjects with idiopathic autism exhibits imbalances in BDNF isoforms, reduced TrkB and downstream effectors PI3 kinase (PI3K), mTOR, Epidermal growth factor receptor pathway substrate 8 (Eps8) and the excitatory synaptic marker postsynaptic density protein 95 kDa (PSD-95). Furthermore, similar TrkB pathway deficits including reduced TrkB/mTOR signaling and PSD-95, along with autistic-like behavior, have been found in valproic acid-exposed rodents, a model of environmental/epigenetic causes of autism. Our studies in both human idiopathic autism and the valproic acid-induced rodent model suggest that decreased signaling through the mTOR pathway can be as damaging as its over-activation. AutismAutism is a lifelong neurodevelopmental disorder characterized by disturbances in social interactions and communication and stereotyped, repetitive patterns of interests, activities and behaviors [1,2]. It is one of a heterogeneous group of disorders called Autism Spectrum Disorders (ASD) that share these characteristics but differ in course, symptom pattern or level of functioning. ASD is perhaps the most common and handicapping neurological disorder of childhood in terms of prevalence, morbidity, outcome and cost to society. ASD represents a significant public health problem and poses a huge burden for education and social service systems. Recent estimates of the prevalence of ASD in the US and Canada (CDC, NEDSAC) were 1 in 68 [3,4]. There is currently no diagnostic test or cure available for autism, and its etiology is unknown.Epidemiological and twin studies point to a major role for genetic factors in ASD [5,6], with a complex pattern of transmission thought to be the result of perhaps as many as 1000 interacting genes [7-9]. Hundreds of rare genetic events that carry increased risk for ASD, many of them arising de novo [10][11][12][13][14], have been identified [15][16][17][18][19][20][21].However, genetic changes account for only half of all autistic cases; environmental influences are responsible for the rema...

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Dysregulation of the IGF‐I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders

Cited by 135 publications

References 73 publications

Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

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