CSF1 and the control of postnatal growth and organ development in the rat

During pregnancy, many major organs of the body gain the many functions that will be necessary for life outside of the womb. Effects on growth at these early stages of life can have profound consequences for adult health. Most of the events that determine final body mass and function are controlled by protein found circulating in blood. This factor is called Insulin Growth Factor-1 (IGF1). Traditional knowledge indicates that this factor is made in the liver in response to growth hormone (GH) signals. We propose that this is not the entire picture and another factor ? Cytokine Stimulating Factor 1 (CSF1) - produced by the immune cells called macrophages contribute to the control the GH/IGF-1 system and thus contribute to the control of postnatal growth. We base this hypothesis on our data indicating that animals which lack CSF1 function have a range of developmental and growth abnormalities in common to animals deficient in GH/IGF-1. Although our preliminary data is compelling, the challenge remains to understand how these various factors interact to control growth. With this knowledge we will be better able to evaluate strategies to overcome growth impairment. To address these goals we aim to exploit new transgenic technologies in the rat. Specifically we will determine the consequence of reducing CSF1 signalling on growth and beneficial effects of elevating CSF1 levels as a possible treatment of impaired growth.

In the third trimester of embryonic development, many major organs mature and develop functions that will be necessary for life outside of the womb. Most of the events that determine final body mass, as well as organ maturation, are controlled by Insulin Growth Factor-1 (IGF1). It is widely accepted that IGF1 is a circulating regulator produced by the liver in response to growth hormone (GH). We propose that through CSF1 activity macrophages contribute to the control the GH/IGF-1 system and thus contribute to the control of postnatal growth. Rats and mice that lack CSF1 signalling are macrophage deficient with many developmental abnormalities in common to animals deficient in GH/IGF-1 signalling. To confirm this view administering CSF-1 to new born mice had increased macrophage numbers and an overall increase of 30-40% in total body weight with corresponding enhanced maturity of organ function. Although this preliminary data is compelling, the challenge remains to understand the mechanistic regulation of the CSF-IGF-GH axis to underpin translation of this knowledge into application. To address these goals we aim to exploit new transgenic technologies in the rat to investigate the consequence of reducing CSF1 signalling on growth and elevating CSF1 levels as treatment of impaired growth. To do this we will exploit the lead position we have at The Roslin Institute in rat ES lines. Using this technology we propose to generate and evaluate both CSF1R-knockout and CSF1R-reporter rats to directly address these goals. This will provide a large animal model to evaluate CSF1-replacement strategies. There is a clear biological focus to this target in providing a basis for future therapeutic applications of CSF1 in humans, but it is also attractive as proof of concept for gene targeting in the rat system.