OUR PROJECTS The human brain is made up of billions of neurons that are organized into complex circuits for higher-order brain functions. These neurons are produced by neural stem cells in a precise temporal and spatial manner during development. Perturbing the genesis of correct numbers and types of neurons may result in the abnormal assembly of neural circuitry and, ultimately, brain deficits. With a focus on neural stem cells and neurogenesis, our lab is interested in (i) elucidating the molecular and cellular mechanisms involved in building the mammalian brain, and (ii) understanding how genetic and environmental perturbations relevant to neurodevelopmental disorders impinge on these processes to influence brain development and function. To dissect the molecular basis of neurogenesis, we use the mouse cerebral cortex as our model system and take a multidisciplinary strategy that integrates the single-gene approach, genome-wide analysis and computational prediction. This allows us to obtain a comprehensive view of gene expression landscape at multi-regulatory levels during brain development. By doing this, we aim to identify translational control networks in neural stem cells that, when dysregulated, contribute to the pathogenesis of neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia.
Departments of Medical Genetics, Biochemistry & Molecular Biology Cumming School of Medicine Alberta Children’s Hospital Research Institute University of Calgary HS-2229 Health Science Centre 3330 Hospital Drive N.W. Calgary, Alberta Canada T2N 4N1 E | info.yanglab@gmail.com
Project 1. The Translational Switch in NPCs for Timely Neurogenesis
How are NPCs regulated for appropriate neurogenesis? Much effort has been made to understand the transcriptional regulation of NPCs during neurogenesis. However, increasing evidence shows that mRNA expression often correlates poorly with protein levels, and that gene regulation at the translational level is equally important for controlling complex cellular functions. In line with this notion, protein synthesis has been found to be altered in some forms of autism due to mutations in genes encoding translational regulators, such as the X-linked familial mental retardation protein FMRP, tuberous sclerosis complex proteins TSC1/2 and the translation initiation factor eIF4E. In the past few years, we identified a group of translational repression complexes in NPCs comprised of the translation regulator eIF4E and its binding partner 4E-T. By binding and translationally suppressing mRNAs that promote neurogenesis, the complex maintains the stem cell state of NPCs while allowing rapid neurogenesis in response to cues that de-repress the complex. This evidence reveals an unexpected transcriptionally-primed state of NPCs and an essential role for translational regulation in enabling appropriate neurogenesis at the correct developmental time. To further elucidate how 4E-T repressive complex in NPCs controls appropriate neurogenesis, we have taken computational prediction and proteomic approaches for identifying regulatory RNA-binding proteins and other putative players in the complex.
Project 2. Translational Regulation of Neuronal Subtype Specification
The assembly of complex cortical circuits requires diverse subtypes of neurons. The genesis of incorrect neuronal subtypes has been linked to the disorganization of cortical layers observed in children with autism. Different subtypes of cortical neurons (deep or superficial layer neurons) are sequentially generated from NPCs at different timepoints by mechanisms that are poorly understood. It is thought that the sequential expression of subtype specification genes in NPCs directs the generation of corresponding neuronal subtypes. Our finding that translational mechanisms play a key role in general aspects of neurogenesis raised the possibility that translational regulation of subtype specification genes in NPCs might also control the temporal genesis of specific neuronal subtype during development. Using systemic analysis of gene expression at both transcription and translation levels, we aim to identify the gene networks and regulators involved in neuronal subtype specification during brain development.
Project 3. Gene-Environment Interaction in Brain Development
While the pathogenesis of many neurodevelopmental disorders is likely to involve interactions between genetic vulnerability and environmental factors experienced during the in-utero developmental period, it is still largely unknown how the adverse prenatal environment interacts with genetic risk factors to influence brain development and function. In this regard, we are interested in how the gene-environment interplay regulates NPCs and neurogenesis in the developing brain. As one example, we have recently focused on maternal diabetes, where a toxic metabolite methylglyoxal is increased in the circulation, and its detoxifying enzyme Glo1 has been implicated in autism. We have found that perturbations of the metabolic Glo1-methylglyoxal pathway disturb NPCs, cortical development and, in the longterm, impair adult neurogenesis and cognitive function in offspring.
Development of the mammalian cerebral cortex involves a series of fine-tuned processes, including the generation of proper numbers and subtypes of neurons from neural stem/precursor cells (NPCs), the placement of these neurons into correct cortical layers, and finally the assembly of neural circuits. Interruption of one or more of these steps may result in cortical malformation and/or long-lasting structural consequences for the mature brain, both of which have a substantial impact on cognition. However, the mechanisms that control NPCs to generate correct numbers of diverse neuronal subtypes in the developing brain are still largely unknown. We, therefore, aim to address this question and further ask how disease-relevant genetic and environmental risk factors interact to influence NPCs and developmental neurogenesis to shape brain structure and function. Our current efforts are divided into three major projects.
1
A Translational Switch for Timely Neurogenesis How do NPCs maintain the balance of self-renewal and differentiation? We study a group of translational repres-sion complexes that direct neurogenesis by controlling gene expression in NPCs at the level of translation.
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2
Translational Specification of Neuronal Subtypes Focusing on translational regulations in cortical NPCs, we study how NPCs specify the identity of diverse neuronal subtypes in a temporally specific manner to populate six cortical layers during development.
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3
Gene-Environment Interaction in Brain Development The prenatal environment has a profound impact on fetal brain development. We are inter- ested in how cell-intrinsic and intrauterine environmental factors interact to affect brain development and function.
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Research
we are grateful for the funding support.
Publications (selected)
MacPherson M.J., Erickson S.L., Kopp D., Wen P, Aghanoori M.R., Kedia S., Burns K.M.L., Vitobello A., Mau-Them F.T., Thomas Q., Gold N.B., Brucker W., Amlie-Wolf L., Gripp K.W., Bodamer O., Faivre L., Muona M., Menzies L., Baptista J., Guegan K., Male A., Wei X.C., He G., Long Q., Innes A.M., Yang G. (2021). Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates. Cell Reports. 35(10), 109226. DOI:https://doi.org/10.1016/j.celrep.2021.109226 Kedia S, Erickson SL, Yang G. (2021). Analysis of translation in the developing mouse brain using polysome profiling. Journal of Visualized Experiments. 22. doi: 10.3791/62088. Rodrigues DC, Harvey E, Suraj R, Erickson S, Mohammad L, Ren M, Liu H, He G, Kaplan D, Ellis J, Yang G. (2020). Methylglyoxal couples metabolic and translational control of Notch signalling in mammalian neural stem cells. Nature Communications. 11. https://doi.org/10.1038/s41467-020-15941-2 Zeng Q, Long Z, Zhao Y, Feng M, Luo S, Wang K, Wang Y, Yang G, He G. (2019). Valproic acid stimulates hippocampal neurogenesis via activating the Wnt/β-catenin signaling pathway in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer’s disease. Frontiers Aging Neuroscience. 11: 62. Mohammad L, Wiseman J, Erickson S, Yang G. (2019). Protein synthesis and translational control in neural stem cell development and neurogenesis. The Oxford Handbook of Neuronal Protein Synthesis. DOI: 10.1093/oxfordhb/9780190686307.013.21. Zahr SK, Yang G, Kazan H, Borrett MJ, Yuzwa SA, Voronova A, Kaplan DR, Miller FD.(2018). A translational repression complex in developing mammalian neural stem cells that regulates neuronal specification. Neuron. 97(3): 520-537. Yang G, Cancino GI, Zahr SK, Guskjolen A, Voronova A, Gallagher D, Frankland PW, Kaplan DR, Miller FD. (2016). A Glo1-methylglyoxal pathway that is perturbed in maternal diabetes regulates embryonic and adult neural stem cell pools in murine offspring. Cell Reports. 17: 1022-1036. Rodrigues DC, Kim DS, Yang G, Zaslavsky K, Ha KC, Mok RS, Ross PJ, Zhao M, Piekna A, Wei W, Blencowe BJ, Morris Q, Ellis J. (2016). MECP2 is post-transcriptionally regulated during human neurodevelopment by combinatorial action of RNA-binding proteins and miRNAs. Cell Reports. 17: 720-734. Amadei G, Zander M, Yang G, Dumelie J, Vessey JP, Lipshitz H, Smibert CA, Kaplan DR, Miller FD. (2015). A Smaug2-based translational repression complex determines the balance between precursor maintenance versus differentiation during mammalian neurogenesis. Journal of Neuroscience. 35: 15666-15681. Yang G, Smibert CA, Kaplan DR, Miller FD. (2014). An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron. 84: 723-739.
Team
Guang Yang, PhD Principal Investigator Canada Research Chair (Tier II, regulatory genomics)
Reza Aghanoori, PhD Post-doc ACHRI/CSM Postdoc Fellowships CIHR Postdoc Fellowship
Laura Williams, MSc Technician
Emily Harvey Graduate student Alberta Graduate Excellence Scholarship
Sarah Erickson, MSc Research assistant
Shreeya Kedia Graduate student Mitacs Globalink Fellowship ACHRI Graduate Scholarship
Drayden Kopp Graduate student BMB Research Excellence Award (co-supervisor: Dr. Quan Long)
Kaylan Burns Graduate student CIHR Canada Graduate Scholarship Alberta Graduate Excellence Scholarship
Maneesha Subha Graduate student International Graduate Tuition Award
Lab Alumni Graduate Students & PDF Rejitha Suraj, PDF (2019-2020) Lamees Mohammad, MSc student (2018-2020), funded by ACHRI Graduate Scholarship, current position: PhD at McGill U Minghao (Michael) Li, MSc student (2017-2020), co-supervisor: Dr. Quan Long (primary), funded by ACHRI Graduate Scholarship and BMB graduate student scholarship, current position: AI specialist Research Staff & Visiting Scholars Brooke Rackel, Research assistant (2018-2019), current position: medical school student Melissa MacPherson, visiting scholar (2019), current position: clinical geneticist/assistant professor, University of Alberta Pengqiang Wen, visiting scholar (2018-2019), current position: senior medical technologist, Shenzhen Institute of Pediatrics Holly Liu, Research assistant (2017), current position: animal facility specialist, University of Calgary Undergraduate/Summer Students Michelle Hua, University of Calgary (2019-2021), funded by NSERC USRA Summer Studentship awards, BCEM 528, Kenedi Sandquist, University of Calgary (2020-2021), MDSC528, honors thesis Elana Sarabin, University of Calgary (2020-2021), CMMB 528 Andrew Hui, University of Calgary (2019-2020), funded by AIHS Summer Studentship award Ali Alotaibi, University of Calgary (2019-2020), honors thesis Abdlaziz Alenezi, University of Calgary (2017-2019), MDSC 417, honors thesis Keevin Lee, University of Calgary (2017-2019), MDSC 417, honors thesis Jose Uriel Perez, University of Calgary (2017-2019), MDSC 417, honors thesis Shaelene Standing, University of Calgary (2019), funded by PURE Summer Studentship award Anna-Maria Ciorogariu-Ivan, Mount Royal University (2019) Jibe Zantua, University of Calgary (2018-2019), MDSC 417 Mohammad Behbehani, University of Calgary (2018-2019), MDSC 417 Carina Jones, University of Calgary (2018), funded by NSERC USRA Summer Studentship award Joscelyn Wiseman, Acadia University (2018), Queen Elizabeth II award Fatin Ishraque, University of Calgary (2018) Mataea Armstrong, High School Summer Student (2018), funded by the Heritage Youth Researcher Summer Program (HYRS) Katherine Liang, High School Summer Student (2017), funded by the Heritage Youth Researcher Summer Program (HYRS)
Opportunity
PhD Student Positions – Gene Regulation in Stem Cell Biology and Brain Development (update: 2021-JUN) About the Project: PhD student positions are available for highly motivated individuals with interest in studying stem cell biology and brain development using a combination of molecular, cellular, genetic, and bioinformatics approaches. The projects will involve utilizing mouse models with transcriptomic and translatomic analysis to dissect gene regulatory mechanisms that control neural stem cell development in the mammalian brain. Another potential avenue of research involves the study of the molecular and cellular basis of rare neurodevelopmental disorders, using patient induced pluripotent stem cell (iPSC)-derived cells and mouse disease models. Qualifications: - BSc or MSc or an equivalent degree in biochemistry, bioinformatics, cell biology, developmental biology, genetics, neuroscience, or a related discipline. - Prior research experience in wet and/or dry labs. Knowledge and experience in biochemistry techniques, molecular cloning, mammalian cell culture, mouse genetics, and confocal microscopy would be highly desirable. Strong programming skills in R and Python, and prior experience with sequencing analysis would be an asset. - Must be self‐motivated, with a keen interest in working on multidisciplinary projects. - A strong academic background. - Proficiency in English. - Excellent communication, written and interpersonal skills. - Willingness to work in an international team. Application details: Please send a single PDF file containing a cover letter describing (i) your previous research experience, (ii) future goals, and (iii) why studying stem cells and brain development is of interest to you, together with your CV, and relevant transcripts to "guang.yang2@ucalgary.ca" with the subject line "PhD Student Position." About the University of Calgary: The University of Calgary is Canada's leading next-generation university – a living, growing and youthful institution that embraces change and opportunity with a can-do attitude. The University of Calgary inspires and supports discovery, creativity and innovation across all disciplines. For more information, visit ucalgary.ca. About Calgary, Alberta: Calgary, Canada's fastest-growing major city, is vibrant and multicultural, with a population of more than 1.2 million. Situated near the Rocky Mountains, Banff National Park and Lake Louise, Calgary offers a great quality of life and outstanding recreational activities. Funding Notes: The students will receive full stipend support and will also be encouraged to apply for internal and external scholarships.

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