# Microglial colonization of the developing mouse brain is controlled by both microglial and neural CSF-1

## TL;DR

This study shows how microglia, the brain's immune cells, colonize the developing mouse brain using both their own and neural sources of a growth factor called CSF-1.

## Contribution

The study reveals that microglial colonization is controlled by both intrinsic and extrinsic CSF-1 sources during brain development.

## Key findings

- Microglia proliferate in transient hotspots during brain development, adopting an ATM-like state.
- Neural CSF-1, produced by cortical progenitor cells and neurons, is essential for embryonic microglial distribution.
- Intrinsic CSF-1 from ATM-like microglia supports their sustained proliferation in hotspots.

## Abstract

Microglia are brain-resident macrophages critical for cerebral development, function, and homeostasis. During development, yolk sac-derived microglial progenitor cells colonize and populate the brain following a well-defined spatiotemporal pattern. However, the mechanisms controlling microglial colonization and proliferation remain largely unknown. Here, we describe two broad waves of microglial proliferation in the developing mouse forebrain. Microglia accumulate in transient hotspots, in a proliferative axon tract-associated microglia (ATM)-like state. Prenatal and early postnatal patterns of microglial colonization do not rely on neuronal activity. Instead, using conditional inactivation of the microglial regulator colony-stimulating factor 1 (Csf1) gene, we reveal that the distribution and proliferation of embryonic cortical microglia critically rely on neural CSF-1, mainly produced by cortical progenitor cells but also by post-mitotic neurons, with the action of CSF-1 being local, dose-dependent, and transient. In addition, intrinsic CSF-1 expressed by ATM microglia contributes to their sustained proliferation in developmental hotspots. Our study reveals that microglia rely on distinct, local, and cell-type-specific sources of CSF-1 for their developmental distribution, which has major implications for understanding how microglia colonize the brain in health and disease.

Microglia are critical for cerebral development and function, but how they colonize the brain during early development remains incompletely understood. This study identifies proliferative niches and uncovers the roles of colony-stimulating factor 1 (CSF1) from different sources in this process.

Microglial colonization exhibits temporally distinct waves of proliferation.Microglia sustain proliferation in transient hotspots, while adopting an axon tract-associated microglia (ATM)-like state marked by Csf1 expression.Extrinsic, neural CSF-1 is transiently required for cortical embryonic microglia.Intrinsic CSF-1 produced by ATM-like cells promotes their proliferation in transient hotspots.

Microglial colonization exhibits temporally distinct waves of proliferation.

Microglia sustain proliferation in transient hotspots, while adopting an axon tract-associated microglia (ATM)-like state marked by Csf1 expression.

Extrinsic, neural CSF-1 is transiently required for cortical embryonic microglia.

Intrinsic CSF-1 produced by ATM-like cells promotes their proliferation in transient hotspots.

Developmental distribution and proliferation of microglia depend on intrinsic and extrinsic sources of colony-stimulating factor 1.