Figure 4:

Two alternative hypotheses for the origin of microglia and BAMs.

a) Hypothesis 1 - EMPs arise from YS-blood islands around E7.5 (1) and at E8.5 migrate into the embryo proper where they differentiate into macrophage precursors (pre-Macs) (2). These cells seed all embryonic tissues including the brain (3). Depending on the local environment, they differentiate into either microglia (4) or BAMs (5). In this model, microglia and BAMs originate from common progenitors and the local environment plays a major role in determining their fate. The genes indicated in boxes 4 and 5 refer to transcriptional signatures identified in the adult mouse brain.

b) Hypothesis 2 - EMPs arise from YS-blood islands around E7.5 (1) and at E8.5 migrate into the embryo proper where they differentiate into macrophage precursors (pre-Macs) (2). These cells generate two separate lineages (x and y) giving rise to either pre-microglia (3) or pre-BAMs (4), which respectively colonize the CNS parenchyma and the brain-blood interfaces. The local environment dictates the final maturation into microglia (5) and BAMs (6). In this model, microglia and BAMs share a common ancestor cell (EMP), but eventually develop through distinct lineages. Therefore, a combination of ontogeny and environment is critical for the fate of both cell types. The genes indicated in boxes 5 and 6 refer to transcriptional signatures identified in the adult mouse brain.