, 1995);

however, as astrocytes are phagocytic cells (al-

, 1995);

however, as astrocytes are phagocytic cells (al-Ali and al-Hussain, 1996), the presence of apoptotic nuclei within astrocytes could be phagocytozed apoptotic neurons. We have observed that majority of prospectively isolated CNS astrocytes (IP-astrocytes) die within 40 hr by apoptosis when cultured without any trophic factors and identified HBEGF and Wnt7a as effective at promoting significant astrocyte survival in vitro. Previous studies have underlined the necessity of EGFR for survival in the cortex; however, the relevant ligand for EGFR has not been identified (Kornblum et al., 1999 and Wagner et al., 2006). Our finding that HBEGF strongly promotes astrocyte survival in vitro, together with Imatinib supplier its high level in vascular cells (Daneman et al., 2010), strongly suggests that HBEGF is an excellent candidate for the ligand mediating astrocyte

survival in vivo. Do developing astrocytes compete for a limiting amount of endogenous trophic factor as do developing neurons and oligodendrocytes, which are matched to a limited number of target cells and axons, respectively (Barres et al., 1992)? Indeed, we have observed astrocytic apoptosis during the peak of astrogenesis in vivo. As we found that HBEGF is highly expressed by developing vascular cells, that vascular cells help promote astrocyte survival, and that the majority of the astrocytes R428 concentration we analyzed contacted blood vessels, we hypothesize that a similar matching may occur between astrocytes and blood vessels. Excess, unneeded astrocytes generated where blood vessels are already ensheathed by other astrocytes may undergo elimination by apoptosis. This hypothesis can be tested in future experiments by assessing whether astrocytes fail to survive in adult mice in which blood vessels are eliminated by exposure to hyperoxia (Ndubuizu et al., 2010). It is generally thought that differentiated astrocytes retain a high ability to proliferate.

This hypothesis is based on the existence of highly proliferative glial CNS tumors and as astrocytes in MD-astrocyte cultures are so highly proliferative. However, we show that prospectively purified postnatal astrocytes cultured in HBEGF, a mitogenic signal, display only a modest ability to proliferate, dividing once every 3 days, while MD-astrocytes divide every 1.4 days. Even after astrocytes had reached their plateau numbers in the CNS by about P14 (Skoff and Knapp no 1991), we found that they still retained this modest ability to divide (data not shown). Thus, most cortical astrocytes are not terminally postmitotic, but have a modest ability to divide (Skoff and Knapp, 1991), in keeping with recent findings on the limited proliferation of reactive astrocytes after brain injury (J. Zamanian, L.C.F., and B.A.B., unpublished data). The function of astrocytes has long been an intriguing mystery. As neurons depend on astrocytes for their survival, it has not been possible to get at their functional roles in vivo simply by deleting them.

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