Molecular Biology Institute Graduate Program, University of California, Los Angeles, Los Angeles, United States
Chia-Ho Lin
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States
Andrey Damianov
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States
Katrina L Adams
Molecular Biology Institute Graduate Program, University of California, Los Angeles, Los Angeles, United States; Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Bennett G Novitch
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
The RNA-binding proteins PTBP1 and PTBP2 control programs of alternative splicing during neuronal development. PTBP2 was found to maintain embryonic splicing patterns of many synaptic and cytoskeletal proteins during differentiation of neuronal progenitor cells (NPCs) into early neurons. However, the role of the earlier PTBP1 program in embryonic stem cells (ESCs) and NPCs was not clear. We show that PTBP1 controls a program of neuronal gene expression that includes the transcription factor Pbx1. We identify exons specifically regulated by PTBP1 and not PTBP2 as mouse ESCs differentiate into NPCs. We find that PTBP1 represses Pbx1 exon 7 and the expression of the neuronal Pbx1a isoform in ESCs. Using CRISPR-Cas9 to delete regulatory elements for exon 7, we induce Pbx1a expression in ESCs, finding that this activates transcription of neuronal genes. Thus, PTBP1 controls the activity of Pbx1 to suppress its neuronal transcriptional program prior to induction of NPC development.
