Neurons require trophic support during neural circuit formation; however, how the cellular milieu contributes to neuronal survival remains unclear. We found that layer V cortical neurons require support from microglia for survival during postnatal development. Specifically, we found that microglia accumulated close to the subcerebral and callosal projection axons in the postnatal brain. Inactivation of microglia by minocycline treatment or transient ablation of microglia in CD11b-DTR transgenic mice led to increased apoptosis, specifically in layer V subcerebral and callosal projection neurons. CX3CR1 in microglia was required for the survival of layer V neurons. Microglia consistently promoted the survival of cortical neurons in vitro. In addition, we identified microglia-derived IGF1 as a trophic factor that maintained neuronal survival. Our results highlight a neuron-glia interaction that is indispensable for network formation during a specific period in the developing brain.

Little is known about the organizational and functional connectivity of the corticospinal (CS) circuits that are essential for voluntary movement. Here, we map the connectivity between CS neurons in the forelimb motor and sensory cortices and various spinal interneurons, demonstrating that distinct CS-interneuron circuits control specific aspects of skilled movements. CS fibers originating in the mouse motor cortex directly synapse onto premotor interneurons, including those expressing Chx10. Lesions of the motor cortex or silencing of spinal Chx10 interneurons produces deficits in skilled reaching. In contrast, CS neurons in the sensory cortex do not synapse directly onto premotor interneurons, and they preferentially connect to Vglut3 spinal interneurons. Lesions to the sensory cortex or inhibition of Vglut3 interneurons cause deficits in food pellet release movements in goal-oriented tasks. These findings reveal that CS neurons in the motor and sensory cortices differentially control skilled movements through distinct CS-spinal interneuron circuits.

Hypoxia-inducible factor 1␣ (HIF-1␣) is essential for vascular development during embryogenesis and pathogenesis. However, little is known about its role in brain development. To investigate the function of HIF-1␣ in the central nervous system, a conditional knockout mouse was made with the Cre/LoxP system with a nestin promoter-driven Cre. Neural cell-specific HIF-1␣-deficient mice exhibit hydrocephalus accompanied by a reduction in neural cells and an impairment of spatial memory. Apoptosis of neural cells coincided with vascular regression in the telencephalon of mutant embryos, and these embryonic defects were successfully restored by in vivo gene delivery of HIF-1␣ to the embryos. These results showed that expression of HIF-1␣ in neural cells was essential for normal development of the brain and established a mouse model that would be useful for the evaluation of therapeutic strategies for ischemia, including hypoxia-mediated hydrocephalus.Oxygen deprivation initiates a wide range of responses to increase oxygen supply, including compensation for the loss of vital energy by alternating the expression of a variety of genes. Many of these hypoxia-inducible genes appear to have a common mode of regulation that involves activation of hypoxiainducible factor 1␣ (HIF-1␣), an oxygen-responsive subunit member of the basic helix-loop-helix PAS (PER-ARNT-SIM) family. HIF-1␣ heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT; HIF-1␤) and plays a key role in maintaining oxygen homeostasis by signaling hypoxic exposure to genes that are involved in angiogenesis, erythropoiesis, glycolysis, and cell survival (10,34,37). In addition to its roles in physiological oxygen homeostasis, HIF-1␣ has also been implicated in the pathogenesis of various diseases, including ischemic heart disease, stroke, and cancer (11,29,33,36).HIF-1␣ is expressed in the developing brain (16) and modulates gene activity in response to low oxygen in a hypoxic brain in vivo. HIF-1␣ has also been implicated as a critical factor in the pathogenesis of brain tumor vascularization and stroke by regulating local brain hypoxia (8,36,38). Although these results indicate that HIF-1␣ is involved in angiogenesis in the brain and neuroprotection, it has not been established whether HIF-1␣ contributes to brain development. Systemic disruption of the Hif-1␣ gene leads to embryonic lethality by day of embryonic development 11 (E11) that is accompanied by cardiovascular malformation and defective cephalic vascularization, indicating that HIF-1␣ is essential for embryonic vascularization (14,21,32). However, the significance of HIF-1␣ in the development of the central nervous system remains unclear.To investigate the function of HIF-1␣ in the central nervous system, a conditional knockout mouse was generated with the Cre/LoxP system with a nestin promoter-based neural precursor-specific Cre recombinase (12). The nestin promoter directs gene expression specifically in neural precursor cells, so that a loxP-flanked (floxed) gene can be disr...