UC Berkeley

Microglia are essential for brain development and homeostasis. Increasing evidence suggests that dysregulated microglia function contributes to neurodevelopmental conditions (NDCs), including autism. One of the most frequently mutated genes identified in NDCs, POGZ, encodes a putative epigenetic regulator and is highly expressed in hematopoietic lineage cells, from which microglia develop. POGZ expression in both the human and mouse brain peaks during prenatal development and global disruption of Pogz in mice elicits behavioral phenotypes relevant to autism. However, the role of Pogz in microglia is not known. Here we use a reverse genetics approach to investigate the role of Pogz in microglia. By generating mice with heterozygous deletion for Pogz in Cx3cr1-expressing cells, which include microglia, we show that Pogz haploinsufficiency in brain myeloid cells is sufficient to induce increased social interaction and cognitive impairments in male, but not female mice. Interestingly, this unique behavioral signature is consistent with behavior phenotypes associated with the rare genetic disorder White-Sutton Syndrome (WHSUS) in humans, caused by de novo POGZ mutations and characterized by an overly friendly demeanor and intellectual disability. Additionally, using shRNA knockdown and CRISPR/Cas9-mediated knockout in vitro, we show that Pogz is required for microglial transcriptional inflammatory response programs, in a potentially signal dependent manner. Together, these results demonstrate a novel, essential and likely sex dependent role for Pogz in microglia-mediated regulation of brain homeostasis and behavior. Thus, we suggest that the behavioral alterations observed in WHSUS result from brain myeloid cell dysfunction.