Figure 5

Microglia, astrocytes, and neurons share a common molecular language within the CNS, and continually communicate via cytokines, chemokines, neurotransmitters and other factors (center circle). Many of the same molecules originally identified for their roles in immune function have now been implicated in neural development; representative examples are conceptualized here (see [48, 81] for comprehensive reviews). (1) Many cytokines are important for progenitor cell maintenance, proliferation, and differentiation. The bone-morphogenic protein (BMP)/transforming growth factor beta (TGFβ) family of cytokines is critical for neural induction [106]. The gp130 receptor and associated ligands are important for progenitor cell maintenance and proliferation [80, 117, 175]. TLR3 is important for maintaining progenitor cell populations and proliferation of dividing cells within the brain [157], and HMGB1, a known ligand for TLR4, impacts cell survival [319]. (2) Cytokines such as IL-1β and the IL-6 family of proteins have a demonstrated role in cytogenesis within the developing brain [50, 198]. IL-1β expression peaks during astrocytogenesis, which is dependent on the presence of amoeboid microglia [109]. Microglia begin to colonize the developing brain as primitive yolk sac macrophages beginning around E9–10 [107]; macrophage colony-stimulating factor (M-CSF) and the CSF-1 receptor are important for this recruitment [107, 250]. (3) Chemokines, in particular CXCL12 and its receptor CXCR4, guide the migration of new neurons in many brain regions, including the cerebellum [166, 321]. (4) MHC I is critical for the activity dependent formation of synapses within the visual cortex, and likely many other brain regions [60, 78, 261]. TNFα released by astrocytes promotes synaptic transmission and affects activity-dependent synaptic scaling [270]. (5) Complement proteins, C1q and C3, tag synapses for elimination [272]. Microglia recognize these proteins via the complement receptor 3 (CD11b), and phagocytose the labeled synapses as a mechanism of synaptic pruning [254]. (6) Microglia are the primary phagocytic cells of the CNS, and thus have an important role in phagocytosing apoptotic debris following programmed cell death, a process that occurs continuously and most abundantly within the developing brain [93]. Programmed cell death likely plays a major role in recruitment of microglia into the CNS [302].