期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2005483118
关键词
16p11.2 deletion; CD47; iPSCs; macrocephaly
资金
- Stanford University School of Medicine, NIH [R35CA220434-04]
- Autism Center of Excellence grant - National Institute of Child Health and Development [P50 HD093079]
- Ludwig Foundation
- Siebel Fellowship
- [R01CA086065]
CNV at the 16p11.2 locus is linked to neuropsychiatric disorders and affects head sizes differently. Study using hiPSCs reveals that overexpression of CD47 in 16p11.2 deletion carriers decreases phagocytosis, suggesting a potential mechanism for brain overgrowth.
Copy number variation (CNV) at the 16p11.2 locus is associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia. CNVs of the 16p gene can manifest in opposing head sizes. Carriers of 16p11.2 deletion tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a dont eat me signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Furthermore, 16p11.2 deletion NPCs and OPCs up-regulate cell surface expression of calreticulin (a prophagocytic eat me signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. While the CD47 pathway is commonly implicated in cancer progression, we document a role for CD47 in psychiatric disorders associated with brain overgrowth.
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