SSA - The role of neural specific Src splice variants in neuronal specification and differentiation.

Lead Research Organisation: University of York
Department Name: Biology

Abstract

(N1-Src and N2-Src) is enriched in neural tissue and high levels of N-Src expression are associated with a favourable prognosis in neuroblastoma, leading to spontaneous differentiation and resolution of the cancer. These observations suggest that N-Srcs regulate neuronal differentiation. Our previous work shows that expression of N1-Src drives neuronal differentiation of cells in culture. Furthermore, N-Src isoform expression is highly regulated during Xenopus neuronal development and N-Src knockdown inhibits neuronal differentiation.
Objectives: To understand the role that N-Src isoforms play in regulating neuronal specification and differentiation in the developing nervous system and cell culture. This basic research will underpin efforts to understand the potential of N-Srcs as regulators of neuronal differentiation in neuroblastoma and stem cells in culture.
Novelty: The normal function of N-Srcs in neuronal differentiation is poorly understood. We bring an exciting combination of expertise to this problem. We have developed reagents that allow us to overexpress and specifically inhibit N-Src activity in the developing embryo and cells in culture. Thus, we are in a uniquely
UNIVERSITY OF YORK
DEPARTMENT OF BIOLOGY
White Rose BBSRC DTP Studentship Bid Form
SBForm_WR BBSRC DTP, V2.0 (Sept 2015) Page 2 of 2
favourable position to undertake this study.
Timeliness: Given that it has recently become apparent that alternative splicing plays a key role in neural development, our proposed study investigating the neural function of Src splice isoforms must be viewed as timely.
Experimental Approaches
1) We will investigate the effects of manipulating N-Src activity on expression of genes in the conserved Xenopus neurogenic pathway. Having identified key N-Src regulated elements in Xenopus, we will investigate their function in N-Src mediated differentiation of mammalian cells in culture.
2) Using N-Src differentiated cells in culture, we will obtain a global view of the N-Src regulated transcriptome. The function of identified targets will then be investigated in the developing embryo and cell.

Publications

10 25 50
publication icon
Lewis PA (2017) N1-Src Kinase Is Required for Primary Neurogenesis in Xenopus tropicalis. in The Journal of neuroscience : the official journal of the Society for Neuroscience

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011151/1 30/09/2015 29/09/2023
1792513 Studentship BB/M011151/1 30/09/2016 30/03/2021 Alastair Robert Pizzey
 
Description The project is looking at the role of n1-Src in development of the nervous system, using Xenopus as a non-mammalian vertebrate model. One of our main techniques for studying the role of n1-Src in development is to prevent expression of the gene and assay for effects. We have discovered that n1-Src is essential for development of the nervous system.

Loss of N1-Src causes a striking absence of primary neurogenesis, implicating N1-Src in the specification of neurons early in neural development. Further investigation implicated n1-Src as a factor required for the correct processing of expressed neuronal genes.

The developmental childhood cancer, neuroblastoma, forms in cells that are derived from an embryonic structure called the neural crest. Expression of n1-Src has been implicated in a positive prognosis in neuroblastomas. We have discovered that n1-Src expression is essential for the correct development of the neural crest.
Exploitation Route n1-Src appears to be involved in the splicing/processing of genes during differentiation of the nervous system and is also linked to neuroblastoma prognosis. With cancers arising when cells fail to differentiate and splicing emerging as a drug-able target, future work could look into the splicing events downstream of N-Srcs to see if they could offer a novel differentiation strategy for treating high risk neuroblastomas.
Sectors Pharmaceuticals and Medical Biotechnology,Other

 
Description BBSRC In Vivo skills award
Amount £5,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 09/2020
 
Description BSDB - The Company of Biologists Travel Grant
Amount £600 (GBP)
Organisation British Society for Developmental Biology 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 05/2018
 
Description PhD Facilities Award
Amount £4,532 (GBP)
Organisation University of York 
Sector Academic/University
Country United Kingdom
Start 07/2017 
End 01/2018
 
Description Poster presentation at an international conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Poster presentation at the International Xenopus Conference at the University of Washington, Seattle, in 2018. Postgraduate students and PIs questioned and discussed my research with me.
Year(s) Of Engagement Activity 2018
 
Description Poster teaser talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact 2 minute poster teaser talk at the White Rose DTP BBSRC symposium at the University of York in December 2019. Presentation to students and researchers from the university of York, Leeds and Sheffield enrolled on the BBSRC White Rose DTP. Lead to people visiting my poster and questioning me on my research.
Year(s) Of Engagement Activity 2019
 
Description University of York Intra-Departmental Talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presented the outcomes of my research at the moment to a group of around 30 students and academics from the Biology Department at the University of York.
Year(s) Of Engagement Activity 2018
 
Description University of York Science Trail 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Around 50 pupils attended the University to participate in a day of hands-on science, and science-related, activities. The aim of the event is to broaden horizons, raise aspirations, and give students the opportunity to participate in science activities that are not available in the classroom.
Year(s) Of Engagement Activity 2018