TABLE 1. Summary of Mu¨ller Glia Speciﬁc and Enriched Genes1 The Journal of Comparative Neurology K. ROESCH ET AL. Veriﬁcation; Speciﬁcity Expression level Gene name ApoE Aqp4 Clu Vimentin Kir2.1 Kir4.1 S100a16 Glul CRLBP-1 Dkk3 Chx-10 Spbc25 Itm2b Apg4b Dbi GPR37 Car2 Abca8a Sox2 Gnai2 Cav Jagn1 2310032F03Rik Synpr Col9a1 Prss2 Ube1c Gnb1l Bing4 Kcnj10 Cts0 Ctsh Rhpn Reference Amaratunga et al., 1996 Nagelhus et al., 1998 Blackshaw et al., 2004 Greenberg et al., 2007 Newman and Reichenbach, 1996 Newman and Reichenbach, 1996 Seigel et al., 1996 Blackshaw et al., 2004 Matsuda et al., 2004 Blackshaw et al., 2004 Rowan et al., 2004 Blackshaw et al., 2004 Blackshaw et al., 2004 ISH ISH, DISH ISH, DISH ISH ISH ISH, DISH ISH, DISH ISH ISH, DISH ISH, DISH ISH ISH, Xgal ISH N/A; high N/A; high, also prog N/A; high N/A; high N/A; high ISH; high N/A; medium N/A; medium N/A; high, subset N/A; high, subset N/A; high, subset N/A; high, subset N/A; high N/A; high N/A; high N/A; high High High High High High High High High High High High High High Low High High High High High High High High High High High High High High High High High High High 230 Category Classical markers New markers Mu¨ller glia enriched 1Literature references for known Mu¨ller glia markers are indicated. Abbreviations: DISH, dissociated cell in situ hybridization; ISH, in situ hybridization; N/A, not done; prog, progenitor cells. tiﬁed in Mu¨ ller glia, such as two members of the lysosomal cystein protease family, cathepsin O (Ctso) and cathepsin H (Ctsh), and rhophilin, which is involved in actin cy- toskeleton reorganization, have been found to be present in this cluster as well. The expression of genes known to encode functions that might be relevant for Mu¨ ller glia physiology was exam- ined. For example, as noted above, there are retinal pro- genitor genes expressed in Mu¨ ller glia, such as Dkk3 and Chx10 (Blackshaw et al, 2004; Rowan and Cepko, 2004), perhaps in keeping with their ability to produce neurons in some species under some conditions, or respond to in- jury by re-entering the cell cycle. Expression of the paired-type homeobox, Pax6, was noted in four out of ﬁve of the single M u¨ller glial cells (Fig. 5). Pax6 is a marker for progenitor cells and also for ganglion cells, amacrine cells, and horizontal cells in the mature retina. It has not been reported to be expressed in mature Mu¨ ller glia. However, expression is consistent with the expression of other progenitor genes in M u¨ller glia. Examination of the expression of cell cycle genes by Mu¨ ller glia showed that cyclinD3, Cdc14A, Cdk10, and Spbc25 were enriched in M u¨ller glia. Several genes of the Notch pathway were expressed in signiﬁcant amounts in Mu¨ ller glia, such as Notch1 and Notch2, and might regu- late the re-entry of Mu¨ ller glia into the cell cycle under speciﬁc (e.g., pathological) conditions (Fig. 4). Growth fac- tors such as Fgfs have been suggested to be important for short-range interactions among retinal cells. The facts that aFGF can be released from rod outer segments by a phosphorylation-dependent mechanism, and that apical processes of Mu¨ ller glial cells surround the photorecep- tors, suggest that these factors may mediate communica- tion between glial cells and neurons (Mascarelli et al., 1991). Fgfs, neurotrophic factors, and growth factor recep- tors are also suggested to be important in M u¨ller glial proliferation (Milenkovic et al., 2003). Activation of sev- eral growth factor- and G-protein-coupled receptors has been shown to induce proliferation in cultured M u¨ller glial cells (Ikeda and Puro, 1994). FGF r1, Ngf R, and Ogfr were highly expressed among M u¨ller glia, whereas Eph and Igfb4 were expressed among a few M u¨ller glial cells. Under pathological conditions, Mu¨ ller glia might addi- tionally act as modulators of the immune and/or inﬂam- matory response. Retinal glial cells have been shown to be a major source of cytokines after retinal detachment (Na- kazawa et al., 2006). Recently, MCP-1 (monocyte chemoat- tractant protein 1) expression was shown in M u¨ller glia after retinal detachment (Nakazawa et al., 2007). Compo- nents of the chemokine system that could be detected in Mu¨ ller glia were Xcr1 and Cxcl16 (Fig. 4). M u¨ller glia might also be involved in the prompt clearing of photore- ceptor debris under pathological conditions. During Dro- sophila development, it has been shown that glial cells engulf degenerating axons through recognition mediated by drpr/ced-1 and ced-6/CED-6 (Awasaki et al., 2006). It has been proposed that apoptotic cells and degenerating axons of mature neurons are removed by a similar mech- anism (Awasaki et al., 2006; MacDonald et al., 2006). The ability of Mu¨ ller glia to phagocytose retinal cell debris and foreign substances has been previously shown in vitro (latex beads) and in vivo (melanin) after retinal detach- ment (Mano and Puro, 1990; Stolzenburg et al., 1992; Francke et al., 2001). However, two of the genes, Megf10 (multiple EGF-like-domains 10)/ced-1 and Abca1 (ATP-