Overexpression of CD47 is associated with brain overgrowth in 16p11.2 deletion syndrome

Abstract

One of the most common genetic linkages associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, occurs at the 16p11.2 locus. Copy number variants (CNVs) of the 16p gene can manifest in opposing head sizes. 16p11.2 deletion carriers 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 'don't eat me' signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. Furthermore, 16p11.2 deletion NPCs and OPCs upregulate cell surface expression of calreticulin (a pro-phagocytic 'eat me' signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. While the CD47 pathway is commonly implicated in cancer progression, we document a novel role for CD47 in regulating brain overgrowth in psychiatric disorders and identify new targets for therapeutic intervention.

Convergent mechanisms of microglia‐mediated synaptic dysfunction contribute to diverse neuropathological conditions

“…Elevated externalized PS and concomitant caspase activation has been reported on synaptosomes isolated from models of AD, 278 and overexpression of CD47 has been linked to 16p11.2 deletions associated with ASDs. 279 Whether and how upstream pathological changes lead to altered CD47 expression or PS exposure at dysfunctional synapses will be of interest for further investigation. One potential mechanism is the activation of local apoptotic signaling cascades at dysfunctional synapses.…”