title: Conserved functional antagonism of CELF and MBNL proteins controls stem cell-specific alternative splicing in planarians.
abstract: In contrast to transcriptional regulation, the function of alternative splicing (AS) in stem cells is poorly understood. In mammals, MBNL proteins negatively regulate an exon program specific of embryonic stem cells; however, little is known about the in vivo significance of this regulation. We studied AS in a powerful in vivo model for stem cell biology, the planarian Schmidtea mediterranea. We discover a conserved AS program comprising hundreds of alternative exons, microexons and introns that is differentially regulated in planarian stem cells, and comprehensively identify its regulators. We show that functional antagonism between CELF and MBNL factors directly controls stem cell-specific AS in planarians, placing the origin of this regulatory mechanism at the base of Bilaterians. Knockdown of CELF or MBNL factors lead to abnormal regenerative capacities by affecting self-renewal and differentiation sets of genes, respectively. These results highlight the importance of AS interactions in stem cell regulation across metazoans.
authors: Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: Jordi
authors: 0000-0002-6770-3929
authors: J
authors: Solana
authors: Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.
authors: Manuel
authors: 0000-0002-2179-2567
authors: M
authors: Irimia
authors: Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: Salah
authors: S
authors: Ayoub
authors: Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: Marta Rodriguez
authors: MR
authors: Orejuela
authors: Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: Vera
authors: V
authors: Zywitza
authors: Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: Marvin
authors: M
authors: Jens
authors: Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.|Universitat Pompeu Fabra, Barcelona, Spain.
authors: Javier
authors: J
authors: Tapial
authors: Donnelly Centre, University of Toronto, Toronto, Canada.
authors: Debashish
authors: D
authors: Ray
authors: Donnelly Centre, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors: Quaid
authors: Q
authors: Morris
authors: Donnelly Centre, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors: Timothy R
authors: TR
authors: Hughes
authors: Donnelly Centre, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors: Benjamin J
authors: BJ
authors: Blencowe
authors: Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
authors: Nikolaus
authors: 0000-0002-4785-4332
authors: N
authors: Rajewsky
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D010932:Planarians / Q000235:genetics* / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*
chemical_list: D016601:RNA-Binding Proteins
keywords: Schmidtea mediterranea; alternative splicing; developmental biology; evolutionary biology; genomics; planaria; post-transcriptional gene regulation; regeneration; stem cells