Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis

被引：30

作者：

Birtele, Marcella ^{[1
,2
]}

Del Dosso, Ashley ^{[1
,2
]}

Xu, Tiantian ^{[1
,2
,3
]}

Nguyen, Tuan ^{[1
,2
]}

Wilkinson, Brent ^{[4
,5
]}

Hosseini, Negar ^{[1
,2
]}

Nguyen, Sarah ^{[1
,2
]}

Urenda, Jean-Paul ^{[1
,2
]}

Knight, Gavin ^{[6
,7
]}

Rojas, Camilo ^{[8
,9
,10
]}

Flores, Ilse ^{[4
,5
]}

Atamian, Alexander ^{[1
,2
]}

Moore, Roger ^{[11
]}

Sharma, Ritin ^{[11
,12
]}

Pirrotte, Patrick ^{[11
,12
]}

Ashton, Randolph S. ^{[6
,7
]}

Huang, Eric J. ^{[13
,14
]}

Rumbaugh, Gavin ^{[8
,9
,10
]}

Coba, Marcelo P. ^{[4
,5
,15
]}

Quadrato, Giorgia ^{[1
,2
]}

机构：

[1] Univ Southern Calif, Keck Sch Med, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90007 USA

[2] Univ Southern Calif, Eli & Edythe Broad, Keck Sch Med, CIRM Ctr Regenerat Med & Stem Cell Res USC, Los Angeles, CA 90007 USA

[3] Cent South Univ, Xiangya Hosp, Changsha, Peoples R China

[4] Univ Southern Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA USA

[5] Univ Southern Calif, Zilkha Neurogenet Inst, Keck Sch Med, Los Angeles, CA USA

[6] Univ Wisconsin Madison, Dept Biomed Engn, Madison, WI USA

[7] Univ Wisconsin Madison, Wisconsin Inst Discovery, Madison, WI USA

[8] Univ Florida, Scripps Biomed Res Inst, Dept Neurosci, Jupiter, FL USA

[9] Univ Florida, Scripps Biomed Res Inst, Dept Mol Med, Jupiter, FL USA

[10] Scripps Res, Skaggs Grad Sch Chem & Biol Sci, Jupiter, FL USA

[11] City Hope Comprehens Canc Ctr, Integrated Mass Spectrometry Shared Resource, Duarte, CA USA

[12] Translat Genom Res Inst, Canc & Cell Biol Div, Phoenix, AZ USA

[13] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA

[14] Univ Calif San Francisco, Eli & Edythe Broad, Inst Stem Cell Res & Regenerat Med, San Francisco, CA USA

[15] Univ Southern Calif, Keck Sch Med, Dept Physiol & Neurosci, Los Angeles, CA USA

来源：

NATURE NEUROSCIENCE | 2023年 / 26卷 / 12期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

OUTER SUBVENTRICULAR ZONE; GTPASE-ACTIVATING PROTEIN; RADIAL GLIA; CRITICAL-PERIOD; CELL DIVERSITY; DOUBLE CORTEX; MATURATION; MIGRATION; MUTATIONS; NETWORK;

D O I：

10.1038/s41593-023-01477-3

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Genes involved in synaptic function are enriched among those with autism spectrum disorder (ASD)-associated rare genetic variants. Dysregulated cortical neurogenesis has been implicated as a convergent mechanism in ASD pathophysiology, yet it remains unknown how 'synaptic' ASD risk genes contribute to these phenotypes, which arise before synaptogenesis. Here, we show that the synaptic Ras GTPase-activating (RASGAP) protein 1 (SYNGAP1, a top ASD risk gene) is expressed within the apical domain of human radial glia cells (hRGCs). In a human cortical organoid model of SYNGAP1 haploinsufficiency, we find dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination and accelerated maturation of cortical projection neurons. Additionally, we confirmed an imbalance in the ratio of progenitors to neurons in a mouse model of Syngap1 haploinsufficiency. Thus, SYNGAP1-related brain disorders may arise through non-synaptic mechanisms, highlighting the need to study genes associated with neurodevelopmental disorders (NDDs) in diverse human cell types and developmental stages.

引用

页码：2090 / 2103

页数：36

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