Blocking Notch signaling with the gamma-secretase inhibitor DAPT prior to the regenerative process blocks the Müller cells re-entry into the cell cycle (Ghai et al., 2010 and Hayes et al., 2007). However, inhibition of Notch signaling after the proliferation has begun causes a higher percentage of cells to differentiate into amacrine cells than in the control retinas, a result much like that described in the previous section on hair cell regeneration in fish and chicks. Thus, Notch activation is critical early in regeneration,

but dysregulated Notch activity might also limit the effectiveness of the process. The above analysis indicates that retinal damage in Adriamycin order both chick and fish causes a somewhat similar response in the Müller cells: they proliferate and upregulate expression of neural progenitor genes and Notch signaling. However, a key difference is that in the fish most of the progeny of the Müller glia differentiate into retinal neurons and sensory receptor cells, whereas in the bird only a small percentage of the progeny of the Müller glia differentiate Screening Library datasheet as neurons, and few, if any, develop into rods or cone photoreceptor cells. Thus, for functional replacement of neurons after damage, the proliferative response of the Müller glia in birds is not very effective. Nevertheless, comparisons between the bird and fish are instructive as we discuss the regenerative response in mammals below. Mammalian

Müller glia show an even more limited regenerative response to injury than birds (Karl and Reh, 2010). In response to neuronal loss, the Müller glia in rodent retina become “reactive” like the astrocytic response to neuronal damage in other regions of the CNS, increasing their expression of GFAP; however, very few of them re-enter the mitotic cell cycle (Dyer and Cepko, 2000, Levine et al., 2000 and Ooto et al., 2004), Nevertheless, when the retinal damage is followed by treatment with specific mitogenic proteins (e.g., EGF, FGF, IGF, Wnt3a), some Müller glial cells are stimulated to proliferate (Close et al., 2005, Close et al., 2006 and Karl et al., 2008). It is also possible to stimulate

Müller glial proliferation in the absence of overt neuronal death with subtoxic doses of mafosfamide alpha-aminoadipic acid (Takeda et al., 2008). In all of these studies, however, only a relatively small number of Müller glia enter the mitotic cell cycle after damage, when compared with the chick or the fish. Like the mammalian inner ear, one of the restrictions on the proliferation of Müller glia is the Cdki, p27kip1, and in the retina, the expression of this inhibitor is known to be driven by TGF-beta (Close et al., 2005, Close et al., 2006 and Levine et al., 2000). Damage to the retina in fish and birds causes Müller glia to undergo a process of regulated reprogramming, allowing them to adopt a retinal progenitor pattern of gene expression that correlates with their ability to regenerate neurons after damage.