Neural stem cells, which differentiate into neurons and glia, are present in the ventricular zone of the embryonal brain. The precise mechanism by which neural stem cells are maintained during embryogenesis remains to be determined. Here, we found that transient misexpression of the basic helix-loop-helix genes Hes1 and Hes5 keeps embryonal telencephalic cells undifferentiated although they have been shown to induce gliogenesis in the retina. These telencephalic cells later differentiate into neurons and astroglia when Hes expression is down-regulated, suggesting that Hes1-and Hes5-expressing cells are maintained as neural stem cells during embryogenesis. Conversely, in the absence of Hes1 and Hes5, neural stem cells are not properly maintained, generating fewer and smaller neurospheres than the wild type. These results indicate that Hes1 and Hes5 play an important role in the maintenance of neural stem cells but not in gliogenesis in the embryonal telencephalon.

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...

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