Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling

Francisco Bustos; Anna Segarra-Fas; Gino Nardocci; Andrew Cassidy; Odetta Antico; Lindsay Davidson; Lennart Brandenburg; Thomas J. Macartney; Rachel Toth; C. James Hastie; Jennifer Moran; Robert Gourlay; Joby Varghese; Renata F. Soares; Martin Montecino; Greg M. Findlay

doi:10.1016/j.devcel.2020.09.025

Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling

Francisco Bustos, Anna Segarra-Fas, Gino Nardocci, Andrew Cassidy, Odetta Antico, Lindsay Davidson, Lennart Brandenburg, Thomas J. Macartney, Rachel Toth, C. James Hastie, Jennifer Moran, Robert Gourlay, Joby Varghese, Renata F. Soares, Martin Montecino, Greg M. Findlay^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Bustos et al. show that SRPK splicing factor kinase has acquired a developmental function— phosphorylating the RNF12 E3 ubiquitin ligase to promote degradation of the transcription factor, REX1. This signaling pathway regulates a neurodevelopmental gene expression program and is mutated in patients with neurodevelopmental disorders.

Original language	English
Pages (from-to)	629-647.e7
Journal	Developmental Cell
Volume	55
Issue number	5
DOIs	https://doi.org/10.1016/j.devcel.2020.09.025
State	Published - 7 Dec 2020
Externally published	Yes

Bibliographical note

Funding Information:
We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust/Royal Society Sir Henry Dale fellowship (211209/Z/18/Z) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC-PPU prize studentship. G.N. and M.M. are supported by research grants ANID/FONDAP/15090007 and FONDECYT/11190998. F.B. and G.M.F. conceived the study and designed the experiments. F.B. A.S.-F. A.C. O.A. L.B. L.D. J.M. R.G. J.V. and G.M.F. performed experiments. G.N. and M.M. analyzed data and prepared figures. T.M. and R.T. performed DNA cloning and CRISPR-Cas9 design. C.J.H. generated reagents. R.S. analyzed mass-spectrometry data. F.B. and G.M.F. wrote the paper. The authors declare no competing interests.

Funding Information:
We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust /Royal Society Sir Henry Dale fellowship ( 211209/Z/18/Z ) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC -PPU prize studentship. G.N. and M.M. are supported by research grants ANID /FONDAP/ 15090007 and FONDECYT / 11190998 .

Publisher Copyright:
© 2020 The Authors

Keywords

development
metazoan evolution
neural development
neurodevelopmental disorders
protein kinase
protein phosphorylation
signal transduction
stem cells
transcriptomics
ubiquitin signaling

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10.1016/j.devcel.2020.09.025

Cite this

Bustos, F., Segarra-Fas, A., Nardocci, G., Cassidy, A., Antico, O., Davidson, L., Brandenburg, L., Macartney, T. J., Toth, R., Hastie, C. J., Moran, J., Gourlay, R., Varghese, J., Soares, R. F., Montecino, M., & Findlay, G. M. (2020). Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling. Developmental Cell, 55(5), 629-647.e7. https://doi.org/10.1016/j.devcel.2020.09.025

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title = "Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling",

abstract = "Bustos et al. show that SRPK splicing factor kinase has acquired a developmental function— phosphorylating the RNF12 E3 ubiquitin ligase to promote degradation of the transcription factor, REX1. This signaling pathway regulates a neurodevelopmental gene expression program and is mutated in patients with neurodevelopmental disorders.",

keywords = "development, metazoan evolution, neural development, neurodevelopmental disorders, protein kinase, protein phosphorylation, signal transduction, stem cells, transcriptomics, ubiquitin signaling",

author = "Francisco Bustos and Anna Segarra-Fas and Gino Nardocci and Andrew Cassidy and Odetta Antico and Lindsay Davidson and Lennart Brandenburg and Macartney, {Thomas J.} and Rachel Toth and Hastie, {C. James} and Jennifer Moran and Robert Gourlay and Joby Varghese and Soares, {Renata F.} and Martin Montecino and Findlay, {Greg M.}",

note = "Funding Information: We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust/Royal Society Sir Henry Dale fellowship (211209/Z/18/Z) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC-PPU prize studentship. G.N. and M.M. are supported by research grants ANID/FONDAP/15090007 and FONDECYT/11190998. F.B. and G.M.F. conceived the study and designed the experiments. F.B. A.S.-F. A.C. O.A. L.B. L.D. J.M. R.G. J.V. and G.M.F. performed experiments. G.N. and M.M. analyzed data and prepared figures. T.M. and R.T. performed DNA cloning and CRISPR-Cas9 design. C.J.H. generated reagents. R.S. analyzed mass-spectrometry data. F.B. and G.M.F. wrote the paper. The authors declare no competing interests. Funding Information: We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust /Royal Society Sir Henry Dale fellowship ( 211209/Z/18/Z ) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC -PPU prize studentship. G.N. and M.M. are supported by research grants ANID /FONDAP/ 15090007 and FONDECYT / 11190998 . Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = dec,

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doi = "10.1016/j.devcel.2020.09.025",

language = "English",

volume = "55",

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Bustos, F, Segarra-Fas, A, Nardocci, G, Cassidy, A, Antico, O, Davidson, L, Brandenburg, L, Macartney, TJ, Toth, R, Hastie, CJ, Moran, J, Gourlay, R, Varghese, J, Soares, RF, Montecino, M & Findlay, GM 2020, 'Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling', Developmental Cell, vol. 55, no. 5, pp. 629-647.e7. https://doi.org/10.1016/j.devcel.2020.09.025

TY - JOUR

T1 - Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling

AU - Bustos, Francisco

AU - Segarra-Fas, Anna

AU - Nardocci, Gino

AU - Cassidy, Andrew

AU - Antico, Odetta

AU - Davidson, Lindsay

AU - Brandenburg, Lennart

AU - Macartney, Thomas J.

AU - Toth, Rachel

AU - Hastie, C. James

AU - Moran, Jennifer

AU - Gourlay, Robert

AU - Varghese, Joby

AU - Soares, Renata F.

AU - Montecino, Martin

AU - Findlay, Greg M.

N1 - Funding Information: We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust/Royal Society Sir Henry Dale fellowship (211209/Z/18/Z) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC-PPU prize studentship. G.N. and M.M. are supported by research grants ANID/FONDAP/15090007 and FONDECYT/11190998. F.B. and G.M.F. conceived the study and designed the experiments. F.B. A.S.-F. A.C. O.A. L.B. L.D. J.M. R.G. J.V. and G.M.F. performed experiments. G.N. and M.M. analyzed data and prepared figures. T.M. and R.T. performed DNA cloning and CRISPR-Cas9 design. C.J.H. generated reagents. R.S. analyzed mass-spectrometry data. F.B. and G.M.F. wrote the paper. The authors declare no competing interests. Funding Information: We thank Nathanael Gray and Tinghu Zhang (Dana-Farber Cancer Institute) for providing SRPKIN-1, Sam Aparicio (University of British Columbia) for CLK-IN-T3, Helen Walden and Viduth Chaugule (University of Glasgow) for fluorescent ubiquitin, and Francisca Cornejo (Universidad Mayor) for hiPSC extracts. We also thank the following colleagues from the University of Dundee: Angus Lamond and Andrea Pawellek for Madrasin, Ron Hay and Emma Branigan for UBE2D1, Miratul Muqit for expertise in mouse neuronal culture, Vicky Cowling and Joana Silva for mouse tissue extracts, Alejandro Brenes for HipSci proteomics data, and Kate Storey for critical reading of the manuscript. G.M.F is supported by a Wellcome Trust /Royal Society Sir Henry Dale fellowship ( 211209/Z/18/Z ) and a Medical Research Council NEW Investigator award (MR/N000609/1). A.S.-F. is supported by a MRC -PPU prize studentship. G.N. and M.M. are supported by research grants ANID /FONDAP/ 15090007 and FONDECYT / 11190998 . Publisher Copyright: © 2020 The Authors

PY - 2020/12/7

Y1 - 2020/12/7

N2 - Bustos et al. show that SRPK splicing factor kinase has acquired a developmental function— phosphorylating the RNF12 E3 ubiquitin ligase to promote degradation of the transcription factor, REX1. This signaling pathway regulates a neurodevelopmental gene expression program and is mutated in patients with neurodevelopmental disorders.

AB - Bustos et al. show that SRPK splicing factor kinase has acquired a developmental function— phosphorylating the RNF12 E3 ubiquitin ligase to promote degradation of the transcription factor, REX1. This signaling pathway regulates a neurodevelopmental gene expression program and is mutated in patients with neurodevelopmental disorders.

KW - development

KW - metazoan evolution

KW - neural development

KW - neurodevelopmental disorders

KW - protein kinase

KW - protein phosphorylation

KW - signal transduction

KW - stem cells

KW - transcriptomics

KW - ubiquitin signaling

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DO - 10.1016/j.devcel.2020.09.025

M3 - Article

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AN - SCOPUS:85095412691

SN - 1534-5807

VL - 55

SP - 629-647.e7

JO - Developmental Cell

JF - Developmental Cell

IS - 5

ER -

Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling

Abstract

Bibliographical note

Keywords

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