The splicing regulator PTBP1 controls the activity of the transcription factor Pbx1 during neuronal differentiation

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Abstract

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.

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Anthony J Linares

Molecular Biology Institute Graduate Program, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Chia-Ho Lin

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Andrey Damianov

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Katrina L Adams

Molecular Biology Institute Graduate Program, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Bennett G Novitch

Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Douglas L Black

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States

For correspondence
dougb@microbio.ucla.edu

Competing interests
Douglas L Black, Reviewing editor, eLife.

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