Defining the contribution of macrophage subsets to myelination of the central nervous system

• Applicant: Dr. Alana Hoffmann
• Subject Area: Developmental Neurobiology ; Experimental Models for the Understanding of Nervous System Diseases ; Immunology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 498972649

Myelin is the insulating membrane surrounding nerve fiber, which supports central nervous system function. There is lack of understanding of the fundamental mechanisms instructing myelin formation. Recent work has implicated a population of central nervous system resident macrophages, termed microglia, being crucial for myelin formation (myelination). However, these studies used non-specific approaches to deplete microglia, which also target other tissue-resident macrophages termed border-associated macrophages. In particular, macrophages associated with the vasculature (perivascular macrophages) are prime candidates for supporting myelin formation, given their proximity to myelin-forming cells migrating along blood vessels. Nonetheless, the contribution of perivascular macrophages to myelination has not yet been investigated and understanding their roles has been hampered by the lack of specific tools. Recently, development of a new mouse model where microglia are specifically absent - yet perivascular macrophages are preserved - has indicated that myelin formation proceeds in the absence of microglia challenging the current consensus of the primary role of microglia in this process. Preliminary single-cell RNA sequencing of all macrophages within areas of developing myelin of the murine brain revealed a distinct cluster of border-associated macrophages which express a growth factor known to promote myelination (insulin-like growth factor-1), suggesting that these cells may contribute to developmental myelination. Therefore, I propose that perivascular macrophages support myelination in development. This hypothesis will be tested by i) characterizing perivascular macrophage dynamics and gene expression in mouse and human developing brain using state of the art ‘on tissue’ transcriptomics, and ii) determining the requirement for perivascular macrophages in myelin formation, assessed by their specific depletion using new transgenic lines. By bridging the fields of neuroimmunology and developmental neuroscience, this project will reveal fundamental contributions of perivascular macrophages to central nervous system development.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professorin Dr. Veronique Miron