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 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 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 disorder and schizophrenia.
Departments of Medical Genetics,
Biochemistry & Molecular Biology
Alberta Children’s Hospital Research Institute
University of Calgary
Health Science Centre
3330 Hospital Drive N.W.
Canada T2N 4N1
T | 403.220.6203
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.
Focusing on translational regulations in cortical NPCs, we study how NPCs specify the identity of diverse neuronal subtypes in a temporal specific manner to populate six cortical layers during development.
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.
The assembly of complex cortical circuits requires diverse subtypes of neurons. 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.
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. 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.
2. 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.
3. Yang G, Zhou X, Zhu J, Liu R, Zhang S, Coquinco A, Chen Y, Wen Y, Kojic L, Jia W, Cynader MS. (2013) JNK3 couples the neuronal stress response to inhibition of secretory trafficking. Science Signaling, 6, ra57.
4. Yang G, Cynader MS. (2011) Palmitoyl acyltransferase zD17 mediates acute ischemic brain injury by regulating JNK activation in a signaling module. Journal of Neuroscience, 31: 11980-11991.
For a full publication list, Click HERE.
Guang Yang, PhD
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Sarah Erickson, MSc
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Lamees Mohammad, BSc
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Michael Li, BSc
(Co-supervisor: Dr. Quan Long)
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Joscelyn Wiseman, BSc
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Pengqiang Wen, MSc
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Holly Liu, PhD
Research Scientist (2017)
Fatin Ishraque, BSc, Undergraduate Summer Student (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).
Highly motivated individuals are welcome to join the Yang lab. We are currently accepting graduate students and postdoctoral fellows.
For the postdoctoral position, a PhD degree in cell biology, developmental biology, or a related field is preferred. Prior experience with generating transgenic mice, early embryo manipulation, stem cells, and/or bioinformatics. First author publications in these fields would be highly desirable. Must be self‐motivated, highly independent, and have excellent communication, written and interpersonal skills.
Please email me (firstname.lastname@example.org) with your CV and a brief description of your research interests.
Our lab also welcomes motivated undergraduate or high-school students for their summer research. Please feel free to email me and discuss the possibility of joining the lab.
© 2016-2018 Guang Yang