ABSTRACT
Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.
Subject(s)
Brain Neoplasms/pathology , Brain/pathology , Interneurons/cytology , Neural Stem Cells/physiology , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathology , Brain/embryology , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Carcinogenesis , Cell Lineage , Cell Proliferation , Disease Progression , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Gene Expression Profiling , Humans , Induced Pluripotent Stem Cells , Interneurons/physiology , Loss of Heterozygosity , Neural Stem Cells/cytology , Organoids , RNA-Seq , TOR Serine-Threonine Kinases/metabolism , Tuberous Sclerosis/drug therapy , Tuberous Sclerosis/metabolism , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 1 Protein/metabolism , Tuberous Sclerosis Complex 2 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/metabolismABSTRACT
Stem cell-specific transcriptional networks are well known to control pluripotency, but constitutive cellular processes such as mRNA splicing and protein synthesis can add complex layers of regulation with poorly understood effects on cell-fate decisions. Here, we show that the RNA binding protein HTATSF1 controls embryonic stem cell differentiation by regulating multiple aspects of RNA processing during ribosome biogenesis. HTATSF1, in a complex with splicing factor SF3B1, controls intron removal from ribosomal protein transcripts and regulates ribosomal RNA transcription and processing, thereby controlling 60S ribosomal abundance and protein synthesis. HTATSF1-dependent protein synthesis is essential for naive pre-implantation epiblast to transition into post-implantation epiblast, a stage with transiently low protein synthesis, and further differentiation toward neuroectoderm. Together, these results identify coordinated regulation of ribosomal RNA and protein synthesis by HTATSF1 and show that this essential mechanism controls protein synthesis during early mammalian embryogenesis.