دورية أكاديمية
أعرض في EDS

The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development.

التفاصيل البيبلوغرافية
العنوان: The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development.
المؤلفون: Schmidt ERE; Department of Neuroscience, Columbia University, New York, USA.; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, USA., Kupferman JV; Department of Neuroscience, Columbia University, New York, USA.; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, USA., Stackmann M; Department of Neuroscience, Columbia University, New York, USA.; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, USA., Polleux F; Department of Neuroscience, Columbia University, New York, USA. fp2304@columbia.edu.; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, USA. fp2304@columbia.edu.; Kavli Institute for Brain Science, Columbia University, New York, NY, 10032, USA. fp2304@columbia.edu.
المصدر: Scientific reports [Sci Rep] 2019 Dec 10; Vol. 9 (1), pp. 18692. Date of Electronic Publication: 2019 Dec 10.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: GTPase-Activating Proteins/*genetics , Synapses/*genetics, Animals ; Cell Line, Tumor ; Evolution, Molecular ; GTPase-Activating Proteins/metabolism ; Gene Duplication/genetics ; Humans ; Mice ; Neurons/metabolism ; Organogenesis ; Primary Cell Culture ; Pyramidal Cells/metabolism ; Pyramidal Cells/physiology ; Synapses/metabolism
مستخلص: Human-specific gene duplications (HSGDs) have recently emerged as key modifiers of brain development and evolution. However, the molecular mechanisms underlying the function of HSGDs remain often poorly understood. In humans, a truncated duplication of SRGAP2A led to the emergence of two human-specific paralogs: SRGAP2B and SRGAP2C. The ancestral copy SRGAP2A limits synaptic density and promotes maturation of both excitatory (E) and inhibitory (I) synapses received by cortical pyramidal neurons (PNs). SRGAP2C binds to and inhibits all known functions of SRGAP2A leading to an increase in E and I synapse density and protracted synapse maturation, traits characterizing human cortical neurons. Here, we demonstrate how the evolutionary changes that led to the emergence of SRGAP2 HSGDs generated proteins that, in neurons, are intrinsically unstable and, upon hetero-dimerization with SRGAP2A, reduce SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, despite only a few non-synonymous mutations specifically targeting arginine residues, SRGAP2C is unique compared to SRGAP2B in its ability to induce long-lasting changes in synaptic density throughout adulthood. These mutations led to the ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.
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معلومات مُعتمدة: R01 NS067557 United States NS NINDS NIH HHS
المشرفين على المادة: 0 (GTPase-Activating Proteins)
0 (SRGAP2 protein, human)
0 (Srgap2 protein, mouse)
تواريخ الأحداث: Date Created: 20191212 Date Completed: 20201123 Latest Revision: 20210110
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC6904453
DOI: 10.1038/s41598-019-54887-4
PMID: 31822692
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-019-54887-4