The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin. Display omitted •The AUTS2 HX repeat recruits P300 for ncPRC1.3-mediated transcription activation•Mutations in the HX repeat phenocopy CREBBP/EP300 mutations in RSTS•NRF1 recruits ncPRC1.3, which activates a subset of genes fostering neuronal development•Recruitment of P300 and ncPRC1.3 is required for neuronal progenitor differentiation Liu et al. report that mutations in the HX repeat of AUTS2 derived from affected individuals disrupt its interaction with P300, thwarting AUTS2-ncPRC1.3-mediated active transcription. Such mutations reflect those in P300 proper with respect to RSTS. Moreover, NRF1-mediated AUTS2 recruitment is paramount for activation of AUTS2-ncPRC1.3 targets and brain development.