Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors

Belinson, Haim; Nakatani, Jin; Babineau, Brooke A.; Birnbaum, Ramon Y.; Ellegood, Jacob; Bershteyn, Marina; McEvilly, Robert J.; Long, Jeffrey M.; Willert, Karl; Klein, Ophir D.; Ahituv, N; Lerch, Jason P.; Rosenfeld, Michael G.; Wynshaw‐Boris, Anthony

doi:10.1038/mp.2015.207

Cited by 65 publications

(64 citation statements)

References 74 publications

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“…S2). Moreover, studies in model organisms clearly show a fetal origin for social behavior deficits (47). Our results are in line with these findings and suggest that, although a higher mutational burden over all genes may have consequences on IQ, mutational burden in a set of genes with a role at critical early developmental stages influences the development of social behavior.…”

Section: B C Asupporting

confidence: 89%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre-and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1, 2). The highly polygenic nature of ASD (3-5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6). However, combined analyses of de novo, inherited, and case-control variation in over 2,500 ASD parentchild nuclear families identified around 100 genes contributing to ASD risk (7-9), converging on pathways implicated in transcriptional regulation and chromatin modeling in addition to synaptic function.The main challenge in the current understanding of genetic architecture of ASD comes from a need to study the interplay between variants with a high effect (for example, recurrent de novo variants) and a background of variants with an intermediate effect but that nevertheless still disrupt proper neuronal development. Essential genes (EGs) or genes that are necessary for successful completion of pre-and postnatal development are prime candi...

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Section: B C Asupporting

confidence: 89%

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Dvl1 −/− 3 +/− mutant mice display reduced social interaction and transient embryonic brain overgrowth, the result of reduced β-catenin transcriptional activity and reduced levels of the transcription factor Brn2 or Pou3f2 35 . To test if BRN2 levels were similarly affected in NPCs from ASD patients with early brain overgrowth, we performed immunocytochemistry for BRN2 on ASD and control NPCs.…”

Section: Resultsmentioning

confidence: 99%

Altered proliferation and networks in neural cells derived from idiopathic autistic individuals

et al. 2016

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Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology, and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation due to dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by IGF-1, a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.

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“…Second, interrogation of other genes in the same pathway, which are not directly involved in ASD from human genetic studies, offers the opportunity to further support that pathway in ASD pathophysiology. For example, while no ASD-specific genetic mutations have been identified in the disheveled genes ( Dvl 1, 2 and 3 ), Dvl1 or Dvl1/3 KO mice display adult social and repetitive behavioral abnormalities, which are the core features of ASD symptoms [67–69]. This type of example lends further evidence that perturbation of the core Wnt signaling transduction molecules like Dvl1/3 can result in ASD-like abnormalities even though they are not directly implicated in human genetic studies.…”

Section: Reviewmentioning

confidence: 99%

“…Stimulants such as Methylphenidate (e.g., Ritalin) can function as a negative regulator of the canonical pathway by activating GSK-3β [124, 125]. In this regard, various GSK-3β inhibitors have been used to rescue neurogenesis defects in mouse models of psychiatric disorders and ASD, which also stimulate canonical Wnt signaling pathways [69]. Taken together, while it is important to be cautious of the multiple mechanisms of action of all of the classes of medications discussed here, it is intriguing to find that all of them either directly or indirectly impact canonical Wnt signaling in the brain to some degree.…”

Section: Reviewmentioning

confidence: 99%

Wnt signaling networks in autism spectrum disorder and intellectual disability

Kwan

Unda

Singh

2016

J Neurodevelop Disord

117

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BackgroundGenetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations).AbstractGiven the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.ConclusionsWe will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology.

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Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors

Cited by 65 publications

References 74 publications

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Altered proliferation and networks in neural cells derived from idiopathic autistic individuals

Wnt signaling networks in autism spectrum disorder and intellectual disability

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