TBRS-associated mutations disrupt cortical interneuron differentiation and neuronal networks.

Pathogenic mutations cause Tatton-Brown-Rahman Syndrome (TBRS), a disorder characterized by intellectual disability and overgrowth of multiple somatic tissues including the brain. However, the functions of DNMT3A during human cortical development remain poorly understood. Here, we utilized newly developed human pluripotent stem cell models of TBRS-associated mutation to define DNMT3A requirements and consequences of mutation during human cortical neuron development.

Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and function.

Pathogenic mutation of the zinc-finger transcription factor ZNF292 is a recently defined contributor to human neurodevelopmental disorders (NDDs). However, the gene's roles in cortical development and regulatory networks under its control were previously undefined. Here, human stem cell models of ZNF292 deficiency, resembling pathogenic haploinsufficiency, are used to derive cortical inhibitory neuron progenitors and neurons.

Autism- and intellectual disability-associated MYT1L mutation alters human cortical interneuron differentiation, maturation, and physiology.

Myelin transcription factor 1 like (MYT1L) is a neuronal transcription factor highly expressed in the developing and adult brain, and, while pathogenic MYT1L mutations cause neurodevelopmental disorders, these have not been characterized in human models of neurodevelopment. Here, we modeled the consequences of pathogenic MYT1L mutation using human stem cell-derived cortical neurons, demonstrating that MYT1L mutation alters the differentiation trajectory, increasing neuronal gene expression, morphological complexity, and synapse production. We also examined consequences of MYT1L mutation in mature cortical interneurons, identifying hallmarks of impaired neuronal identity and maturation and correspondingly altered channel expression and electrophysiological properties.

Autism and Intellectual Disability-Associated Mutation Alters Human Cortical Interneuron Differentiation, Maturation, and Physiology.

MYT1L is a neuronal transcription factor highly expressed in the developing and adult brain. While pathogenic mutation causes neurodevelopmental disorders, these have not been characterized in human models of neurodevelopment. Here, we defined the consequences of pathogenic mutation in human pluripotent stem cell-derived cortical interneurons.

Defining cis-regulatory elements and transcription factors that control human cortical interneuron development.

Although human cortical interneurons (cINs) are a minority population in the cerebral cortex, disruption of interneuron development is a frequent contributor to neurodevelopmental disorders. Here, we utilized a model for deriving cINs from human embryonic stem cells to profile chromatin state changes and generate an atlas of -regulatory elements (CREs) controlling human cIN development. We used these data to define candidate transcription factors (TFs) that may bind these CREs to regulate interneuron progenitor specification.