Elucidating the role of macrophages during salivary gland development

The correct growth, morphogenesis and patterning of an organ or tissue during development is essential for its function in adulthood. The majority of organs (such as heart, lungs, intestine), develop during the embryonic period in order to be functional by birth, while others (e.g. lymphoid structures and the salivary glands) continue to mature into the neonatal period or into puberty (such as the mammary glands). The salivary glands (SG) develop through a process known as branching morphogenesis, where the glandular epithelium undergoes rounds of branching and clefting, to create a branched organ which is capable, by the time of weaning, of saliva production. A number of precisely timed signalling events are necessary for this correct growth and patterning, and the phenomenon involves multiple cells working together. Recent studies have implicated macrophages (Mf) as having a pivotal role in organ development, in addition to their classical phagocytic roles. Mouse mammary gland Mf are recruited to the epithelium and provide vital cues for branching morphogenesis during embryogenesis. Furthermore, Mf-deficient mice experience altered mammary gland branching and elongation during puberty and pregnancy, resulting in a lactational defect. Similarly, Mf are recruited to the developing pancreas and kidney, and their absence results in abnormal development. While we have recently explored the role of Mf in SG regeneration, and we have shown that Mf are necessary for efficient epithelial regeneration after injury in adulthood, it is not known whether Mf play a key role in SG development. In preliminary data we have shown, for the first time, that a mouse model which exhibits macrophage deficiency (the Csf1rFIRE/FIRE mouse) displays aberrant SG development. Thus, in this project we will ascertain how macrophages influence salivary gland development and branching morphogenesis. We will address this question via 3 aims: Aim 1: Characterise how SG development occurs in the absence of macrophages Aim 2: Interrogate the nature of macrophage-epithelial dialogue during SG development Aim 3: Explore whether exogenous replacement of macrophages or growth factors can mitigate against SG developmental delay While work continues to understand better the processes of SG epithelial development and the key signalling pathways involved, to date there has been no exploration of the involvement of immune cells, despite evidence showing that such interactions, particularly with relevance to macrophages, are important in the development of other organs. The findings of this project will provide a better understanding of the precise processes of SG branching morphogenesis and will ascertain the involvement of macrophages therein. Furthermore, the project will generate a number of datasets which will be widely available and will be of interest both to researchers working in the field of SGs and to those working in related fields, such as developmental biology and immunology.