Investigating FGF ERK MAP kinase signalling in vertebrate skeletal muscle differentiation
Lead Research Organisation:
University of East Anglia
Department Name: Biological Sciences
Abstract
All vertebrates, including human, contain many different cells with specialized functions. We want to understand how these different cell types arise from a single cell, the fertilized egg, during embryonic development.
We know that cells in an embryo are told what to do by so-called signalling molecules. Many of these signals have been discovered in model organisms, and it is clear that the same signals are important to control human development.
Interestingly, one specific signal can cause many different cellular responses. We think that it will be important to understand the mechanisms behind this, so that we might be able to control the differentiation of cells in culture.
We will investigate how fibroblast growth factor (FGF) signals control the growth and differentiation of skeletal muscle cells during chick embryo development. This will help to identify the components required to make healthy skeletal muscle and should help to understand the mechanisms used during muscle regeneration and repair.
We hope that in future the knowledge gained from our research will help to develop new therapies for people with muscle wasting, which happens because of long-term illness or old age.
We know that cells in an embryo are told what to do by so-called signalling molecules. Many of these signals have been discovered in model organisms, and it is clear that the same signals are important to control human development.
Interestingly, one specific signal can cause many different cellular responses. We think that it will be important to understand the mechanisms behind this, so that we might be able to control the differentiation of cells in culture.
We will investigate how fibroblast growth factor (FGF) signals control the growth and differentiation of skeletal muscle cells during chick embryo development. This will help to identify the components required to make healthy skeletal muscle and should help to understand the mechanisms used during muscle regeneration and repair.
We hope that in future the knowledge gained from our research will help to develop new therapies for people with muscle wasting, which happens because of long-term illness or old age.
Technical Summary
Fibroblast growth factor (FGF) mediated signalling via the ERK MAP kinase cascade is important during vertebrate skeletal muscle differentiation. Cell based experiments suggest that FGFs control the balance between proliferation and differentiation of committed progenitors including skeletal myoblasts. However, the detailed function of this pathway during myogenesis in the developing embryo is not completely understood and we will characterise its role in skeletal muscle differentiation and growth. In previous studies, we found that the levels of active ERK MAP kinase are crucial for the cellular response. Using gain- and loss-of-function approaches, we will investigate the role of feedback regulation of ERK signalling in muscle differentiation and examine the function of known negative regulators. This will employ in ovo electroporation of expression constructs, retrovirus mediated infections (RCAS) and siRNA mediated gene knock-down, followed by gene expression analysis using well established markers by both in situ hybridisation, immunohistochemistry and microscopy. In addition, we will use reporter assays, in cell based systems and in the whole embryo, to test the hypothesis that myotome specific microRNAs are involved in controlling FGF signalling strength by targeting components of the transduction cascade. A more detailed understanding of the fundamental mechanisms that control muscle differentiation could potentially be exploited in the development of treatments for muscle degenerative disease and muscle wasting.
