Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes

Abstract

Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.

Altered hippocampal-prefrontal communication during anxiety-related avoidance in mice deficient for the autism-associated gene Pogz

“…We found that these mice exhibit altered behavior in a well-studied assay of anxiety-related avoidance, the elevated plus maze (EPM). Interestingly, this is similar to a recently published study which found evidence for decreased anxiety in Pogz mutants using the open field test ( Matsumura et al, 2020 ). We then studied communication between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC), which is known to be necessary for normal anxiety-related avoidance in the EPM.…”

“…Interestingly, another study characterizing mice with heterozygous disruptions of Pogz was recently published ( Matsumura et al, 2020 ). These Pogz mutant mice spent more time in the center of an open field, less time sniffing novel mice, and more time grooming, compared to wild-type mice.…”

Widespread labeling and genomic editing of the fetal central nervous system by in utero CRISRP AAV9-PHP.eB administration

“…AAV9-PHP.eB virus expressing mCherry and the gRNA targeting Pogz was delivered to a transgenic mouse line that constitutively expresses CAS9 protein ( Chiou et al, 2015 ). Because Pogz functions as a negative regulator of transcription and plays crucial roles in embryogenesis, transgenic mice (homozygous for either gene deletion or LoF point mutation) were 100% prenatally lethal ( Matsumura et al, 2020 ; Gudmundsdottir et al, 2018 ). In contrast, Pogz iCAP mice that were identified by mCherry+ under the fluorescent lamp at P1 were viable and showed no signs of evident developmental impairments.…”

Linking Autism Risk Genes to Disruption of Cortical Development

“…Another top ASD gene, POGZ (Pogo transposable element-derived protein with zinc finger domain; OMIM 616364; [ 26 , 27 , 28 , 37 ]), also favors neuronal differentiation by inhibiting the Notch signaling. IUE-mediated knockdown of Pogz leads to an increased proportion of NSCs, and reduced IPs and late-born neurons [ 130 ]. A murine Pogz rescued this phenotype, while mutants carrying ASD pathogenic mutations did not [ 130 ].…”

“…IUE-mediated knockdown of Pogz leads to an increased proportion of NSCs, and reduced IPs and late-born neurons [ 130 ]. A murine Pogz rescued this phenotype, while mutants carrying ASD pathogenic mutations did not [ 130 ]. In line with these data, NSCs derived from induced pluripotent stem cells of a patient with ASD carrying a de novo missense mutation in POGZ also show increased proliferation and reduced degree of neuronal differentiation [ 130 ].…”