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

Marcella Birtele; Ashley Del Dosso; Tiantian Xu; Tuan Nguyen; Brent Wilkinson; Negar Hosseini; Sarah Nguyen; Jean-Paul Urenda; Gavin Knight; Camilo Rojas; Ilse Flores; Alexander Atamian; Roger Moore; Ritin Sharma; Patrick Pirrotte; Randolph S Ashton; Eric J Huang; Gavin Rumbaugh; Marcelo P Coba; Giorgia Quadrato

doi:10.1038/s41593-023-01477-3

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

Nat Neurosci. 2023 Dec;26(12):2090-2103. doi: 10.1038/s41593-023-01477-3. Epub 2023 Nov 9.

Authors

Marcella Birtele^#^{1

2}, Ashley Del Dosso^#^{1

2}, Tiantian Xu^{1

2

3}, Tuan Nguyen^{1

2}, Brent Wilkinson^{4

5}, Negar Hosseini^{1

2}, Sarah Nguyen^{1

2}, Jean-Paul Urenda^{1

2}, Gavin Knight^{6

7}, Camilo Rojas^{8

9}, Ilse Flores^{4

5}, Alexander Atamian^{1

2}, Roger Moore¹⁰, Ritin Sharma^{10

11}, Patrick Pirrotte^{10

11}, Randolph S Ashton^{6

7}, Eric J Huang^{12

13}, Gavin Rumbaugh^{8

9}, Marcelo P Coba^{4

5

14}, Giorgia Quadrato^{15

16}

Affiliations

¹ Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
⁷ Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.
⁸ Departments of Neuroscience and Molecular Medicine, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA.
⁹ Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, Jupiter, FL, USA.
¹⁰ Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹¹ Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
¹² Department of Pathology, University of California, San Francisco, CA, USA.
¹³ Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, CA, USA.
¹⁴ Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁵ Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. quadrato@usc.edu.
¹⁶ Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. quadrato@usc.edu.

^# Contributed equally.

PMID: 37946050
DOI: 10.1038/s41593-023-01477-3

Abstract

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.

MeSH terms

Animals
Autism Spectrum Disorder* / genetics
Humans
Mice
Neurodevelopmental Disorders* / genetics
Neurogenesis / genetics
Phenotype
ras GTPase-Activating Proteins / genetics

Substances

ras GTPase-Activating Proteins
SYNGAP1 protein, human
Syngap1 protein, mouse

Grants and funding

P01 NS083513/NS/NINDS NIH HHS/United States