A novel role for Gab2 in bFGF-mediated cell survival during retinoic acid–induced neuronal differentiation

Gab proteins amplify and integrate signals stimulated by many growth factors. In culture and animals, retinoic acid (RA) induces neuronal differentiation. We show that Gab2 expression is detected in neurons in three models of neuronal differentiation: embryonic carcinoma (EC) stem cells, embryonic stem cells, and primary neural stem cells (NSCs). RA treatment induces apoptosis, countered by basic FGF (bFGF). In EC cells, Gab2 silencing results in hypersensitivity to RA-induced apoptosis and abrogates the protection by bFGF. Gab2 suppression reduces bFGF-dependent activation of AKT but not ERK, and constitutively active AKT, but not constitutively active MEK1, reverses the hypersensitization. Thus, Gab2-mediated AKT activation is required for bFGF's protection. Moreover, Gab2 silencing impairs the differentiation of EC cells to neurons. Similarly, in NSCs, Gab2 suppression reduces bFGF-dependent proliferation as well as neuronal survival and production upon differentiation. Our findings provide the first evidence that Gab2 is an important player in neural differentiation, partly by acting downstream of bFGF to mediate survival through phosphoinositide 3 kinase–AKT

Dixdc1 Is a Critical Regulator of DISC1 and Embryonic Cortical Development

The psychiatric illness risk gene Disrupted in Schizophrenia-1 (DISC1) plays an important role in brain development; however, it is unclear how DISC1 is regulated during cortical development. Here, we report that DISC1 is regulated during embryonic neural progenitor proliferation and neuronal migration through an interaction with DIX domain containing-1 (Dixdc1), the third mammalian gene discovered to contain a Disheveled-Axin (DIX) domain. We determined that Dixdc1 functionally interacts with DISC1 to regulate neural progenitor proliferation by co-modulating Wnt-GSK3β/β-catenin signaling. However, DISC1 and Dixdc1 do not regulate migration via this pathway. During neuronal migration, we discovered that phosphorylation of Dixdc1 by cyclin-dependent kinase 5 (Cdk5) facilitates its interaction with the DISC1-binding partner Ndel1. Furthermore, Dixdc1 phosphorylation and its interaction with DISC1/Ndel1 in vivo is required for neuronal migration. Together, these data reveal that Dixdc1 integrates DISC1 into Wnt-GSK3β/β-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.Human Frontier Science Program (Strasbourg, France) (Long-Term Fellowship)Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)National Alliance for Research on Schizophrenia and Depression (U.S.) (Young Investigator Award)National Institutes of Health (U.S.) (Grant NS37007

Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling

The Disrupted in Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3β. First, DISC1 inhibits GSK3β activity through direct physical interaction, which reduces β-catenin phosphorylation and stabilizes β-catenin. Importantly, expression of stabilized β-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3β/β-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.National Alliance for Research on Schizophrenia and Depression (U.S.) (Young Investigator Award)Natural Sciences and Engineering Research Council of Canada (Postdoctoral Award)Human Frontier Science Program (Strasbourg, France) (Fellowship)Singleton FellowshipNational Institutes of Health (U.S.) (Grant NS37007

Compressed glassy carbon: An ultrastrong and elastic interpenetrating graphene network

Carbon’s unique ability to have both sp2 and sp3 bonding states gives rise to a range of physical attributes, including excellent mechanical and electrical properties. We show that a series of lightweight, ultrastrong, hard, elastic, and conductive carbons are recovered after compressing sp2-hybridized glassy carbon at various temperatures. Compression induces the local buckling of graphene sheets through sp3 nodes to form interpenetrating graphene networks with long-range disorder and short-range order on the nanometer scale. The compressed glassy carbons have extraordinary specific compressive strengths—more than two times that of commonly used ceramics—and simultaneously exhibit robust elastic recovery in response to local deformations. This type of carbon is an optimal ultralight, ultrastrong material for a wide range of multifunctional applications, and the synthesis methodology demonstrates potential to access entirely new metastable materials with exceptional properties

A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors

BACKGROUND: Nonsense mediated mRNA decay (NMD) is an RNA surveillance mechanism that controls RNA stability and ensures the speedy degradation of erroneous and unnecessary transcripts. This mechanism depends on several core factors in the exon junction complex (EJC), eIF4A3, RBM8a, Magoh, and BTZ, as well as peripheral factors to distinguish premature stop codons (PTCs) from normal stop codons in transcripts. Recently, emerging evidence has indicated that NMD factors are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the mechanism in which these factors control embryonic brain development is not clear. RESULT: We found that RBM8a is critical for proliferation and differentiation in cortical neural progenitor cells (NPCs). RBM8a is highly expressed in the subventricular zone (SVZ) of the early embryonic cortex, suggesting that RBM8a may play a role in regulating NPCs. RBM8a overexpression stimulates embryonic NPC proliferation and suppresses neuronal differentiation. Conversely, knockdown of RBM8a in the neocortex reduces NPC proliferation and promotes premature neuronal differentiation. Moreover, overexpression of RBM8a suppresses cell cycle exit and keeps cortical NPCs in a proliferative state. To uncover the underlying mechanisms of this phenotype, genome-wide RNAseq was used to identify potential downstream genes of RBM8a in the brain, which have been implicated in autism and neurodevelopmental disorders. Interestingly, autism and schizophrenia risk genes are highly represented in downstream transcripts of RBM8a. In addition, RBM8a regulates multiple alternative splicing genes and NMD targets that are implicated in ASD. Taken together, this data suggests a novel role of RBM8a in the regulation of neurodevelopment. CONCLUSIONS: Our studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13064-015-0045-7) contains supplementary material, which is available to authorized users

The scaffolding molecule, Gab2, is a key regulator in neural stem cell biology and hematopoietic cell signaling.

Stem cells play important roles in the development and maintenance of many tissues in mammals. Neural stem cells (NSCs) have been isolated from two neurogenic zones in the adult brain, the subventricular zone (SVZ) and the hippocampal dentate gyrus. In the presence of basic Fibroblast Growth Factor (bFGF) or Epidermal Growth Factor (EGF), these cells self renew in vitro and exhibit multipotency. How growth factors regulate stem cell self renewal and differentiation remains poorly understood. In my first project, I have addressed this question by examining the role of an important class of signaling molecules using in vitro stem cell models. The Gab family of docking proteins couples growth factor receptors to essential signaling pathways. Retinoic acid (RA) promotes pluripotent cells such as P19 and embryonic stem (ES) cells to adopt a neural fate. We found that Gab2 expression was significantly increased when P19 or ES cells were induced by RA to differentiate along the neural lineage. Moreover, Gab2 was expressed mainly in neurons, suggesting that Gab2 maybe involved in neuronal differentiation. Using RNA interference, Gab2 silencing impaired the ability of P19 cells to undergo neuronal differentiation. Next, we examined the role of Gab2 in NSCs. Compared to undifferentiated ES or P19 cells, Gab2 levels were much higher in NSCs. Using the neurosphere colony assay, Gab2 silencing significantly reduced the ability of NSCs to form bFGF-dependent neurospheres. Additionally, Gab2 silencing specifically increased neuronal but not glial apoptosis, leading to a significant reduction in neuron production. Our study provides new insights into how growth factors diversify their functions through adaptor proteins to regulate neurogenesis. In my second project, I studied the role of Gab2 in myeloid cells. We found that Gab2 is required for optimal Colony Stimulating Factor-1 (CSF-1)-mediated cell proliferation, but not that dependent on interleukin-3. Gab2 knockdown reduced AKT but not ERK activation in response to CSF-1. Overexpression of Gab2 stimulates CSF-1-mediated proliferation, but this is not correlated with increased AKT activity. Our results suggest that Gab 2 is required for CSF-1-induced AKT activation, and regulates cell proliferation through both AKT-dependent and -independent pathways.Ph.D.Health and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125439/2/3192719.pd

Dissecting Molecular Genetic Mechanisms of 1q21.1 CNV in Neuropsychiatric Disorders

Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance

Design model execution engine based on web services for distributed geography modeling environment

The design of execution engine based on web services for distributed geography modeling environment relies on model contract, model management environment, execution node, data center and control node. The execution procedure of geography model execution engine would be like this: first, geographers construct model contract according to the rule of model contract, and then submit the model contract into control node; Second, the control node parsers the model contract, queries the geography model deployment information, entry point and model input/output information from model management environment, keeps them in memory; Third, control node prepares model data and calls the models which distributed on each execution node for simulation; Finally, the environment returns the result to geographers. The model execution engine adopts multi-thread technology, and could handle multi-job submitted by geographers.Engineering, Electrical & ElectronicGeosciences, MultidisciplinaryRemote SensingEICPCI-S(ISTP)

Public Perceptions of Cryosphere Change and the Selection of Adaptation Measures in the Ürümqi River Basin

This study focuses on the characters of public perceptions on climate and cryosphere change, which are based on a questionnaire survey in the Ürümqi River Basin. In comparison with scientific observation results of climate and cryosphere change, this paper analyzes the possible impact of the change on water resources and agriculture production in the area. Perceptions of most respondents on climate and cryosphere changes confirm the main objective facts. For the selection of adaptation measures addressing the shortage of water resource, the results are as follows: most people preferred to choose the measures like “policy change” and “basic facility construction” which are mostly implemented by the government and the policy-making department, some people showed more preference to the measures of avoiding unfavorable natural environment, such as finding job in or migrating to other places. The urgency of personal participation in the adaptation measures is still inadequate. Some adaptation measures should be implemented in line with local conditions and require the organic combination of “resource-development” with “water-saving”. Deng, M., H. Zhang, W. Mao, et al., 2011: Public perceptions of cryosphere change and the selection of adaptation measures in the Ürümqi River Basin. Adv. Clim. Change Res., 2(3), doi: 10.3724/SP.J.1248.2011.00149