Age‐specific function of α5β1 integrin in microglial migration during early colonization of the developing mouse cortex

Abstract

Microglia, the immune cells of the central nervous system, take part in brain development and homeostasis. They derive from primitive myeloid progenitors that originate in the yolk sac and colonize the brain mainly through intensive migration. During development, microglial migration speed declines which suggests that their interaction with the microenvironment changes. However, the matrix-cell interactions allowing dispersion within the parenchyma are unknown. Therefore, we aimed to better characterize the migration behavior and to assess the role of matrix-integrin interactions during microglial migration in the embryonic brain ex vivo. We focused on microglia-fibronectin interactions mediated through the fibronectin receptor α5β1 integrin because in vitro work indirectly suggested a role for this ligand-receptor pair. Using 2-photon time-lapse microscopy on acute ex vivo embryonic brain slices, we found that migration occurs in a saltatory pattern and is developmentally regulated. Most importantly, there is an age-specific function of the α5β1 integrin during microglial cortex colonization. At embryonic day (E) 13.5, α5β1 facilitates migration while from E15.5, it inhibits migration. These results indicate a developmentally regulated function of α5β1 integrin in microglial migration during colonization of the embryonic brain.

Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity

“…At each stage of development, microglia evolve distinct pathways for processing relevant signals from the environment and to maintain homeostasis within the brain. This was supported by a recent study demonstrating that function of a5b1 integrin in microglia varies based on age during early colonization of the developing mouse cortex, based on microglial migration levels (Smolders et al, 2017). This is relevant because neurological disorders are increasingly viewed as originating from disrupted normal developmental trajectory or disrupted maturation of glial cells as well as neurons (Marin, 2016 disorder and schizophrenia (Gandal et al, 2012 Another important observation in the current study was that, at least in the case of LPS treatment, there was a distinction between an LPS response that was shared between males and females and a LPSinduced developmental response that occurred only in males.…”

“…At each stage of development, microglia evolve distinct pathways for processing relevant signals from the environment and to maintain homeostasis within the brain. This was supported by a recent study demonstrating that function of α5β1 integrin in microglia varies based on age during early colonization of the developing mouse cortex, based on microglial migration levels (Smolders et al, 2017). This is relevant because neurological disorders are increasingly viewed as originating from disrupted normal developmental trajectory or maturation of glial cells as well as neurons (Marin, 2016).…”

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

“…Secreted factors, such as colony‐stimulating factor 1 and interleukin‐34, are necessary for microglia viability (Elmore et al, ; Erblich, Zhu, Etgen, Dobrenis, & Pollard, ; Greter et al, ; Wang et al, ; Wei et al, ), and other factors, such as transforming growth factor‐beta, promote their maturation into an adult phenotype (Bohlen et al, ; Butovsky et al, ). Microglia colonization is influenced by a number of developmental phenomena—maturation of cell surface markers and secreted factors, progenitor cell proliferation, and apoptosis—in a brain‐region‐ and time‐dependent manner (Arnó et al, ; Ashwell, ; Eyo, Miner, Weiner, & Dailey, ; Ferrer et al, ; Hoshiko et al, ; Lelli et al, ; Mosher et al, ; Perry, Hume, & Gordon, ; Smolders et al, ). Together, these environmental signals serve to coordinate the timing of microglia entry and function in parallel with the maturation of specific brain regions.…”

Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system

“…Microglia phagocytosis function will be covered in more detail further down. During the early phase of development, the density of microglia is rather low, which is compensated by their increased mobility [ 81 ]. Depending on timing and developmental processes, there is a corresponding dynamic spatial patterning of microglia [ 82 – 84 ].…”