Reduced Layer 4 Neurogenesis of the Primary Somatosensory and Primary Visual Cortex in Mice with Sall1 deficient microglia

Abstract

Microglia are the resident macrophages of the central nervous system (CNS) that emigrate into the brain until the formation of the blood-brain barrier, where they undergo final maturation and differentiation. Microglia are known to be involved in formation and maintenance of neuronal circuits, repair after injury, and neurogenesis. However, not much is known about the mechanisms of early microglia development and their effects on early neural cell development. Through gene expression profiling, the spalt-like transcription factor 1 (Sall1) gene has been identified as a signature microglial gene, as other members of the mononuclear phagocyte family do not express it. Our lab recently found that Sall1 is essential for normal morphological and molecular maturation of developing microglia. Thus, Sall1 conditional knockout (cKO) mice can be used to test the requirement of normal microglia development in neural cell development. Using these mice, we are analyzing neurogenesis in the neocortex and synaptic pruning in the visual system. In postnatal (P8) Primary Somatosensory (S1) and Primary Visual (V1) cortex, we found that there is a significant reduction in the neurogenesis of layer 4 (L4) neurons (S1: p=0.007, n=11; V1: p=0.034, n=9). This suggests that normal microglial development is required for normal neuron development. To investigate the cellular mechanism for such a role in microglia, we are analyzing brains in which the neurons are birth-dated by 5-Ethynyl-2′-deoxyuridine (EdU) at E14.5. In addition, we plan on analyzing different developmental stages, like P1, to learn whether the impeded development mechanisms are embryonic or postnatal. Lastly, we are analyzing early postnatal visual thalamus, where retinogeniculate axons from the two eyes are segregated in an activity- and microglia-dependent manner, using Cholera toxin subunit B (CTB) injection.