Sonic Hedgehog Regulates Discrete Populations of Astrocytes in the Adult Mouse Forebrain

Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, New York 10065, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2010; 30(41):13597-608. DOI: 10.1523/JNEUROSCI.0830-10.2010
Source: PubMed


Astrocytes are an essential component of the CNS, and recent evidence points to an increasing diversity of their functions. Identifying molecular pathways that mediate distinct astrocyte functions, is key to understanding how the nervous system operates in the intact and pathological states. In this study, we demonstrate that the Hedgehog (Hh) pathway, well known for its roles in the developing CNS, is active in astrocytes of the mature mouse forebrain in vivo. Using multiple genetic approaches, we show that regionally distinct subsets of astrocytes receive Hh signaling, indicating a molecular diversity between specific astrocyte populations. Furthermore, we identified neurons as a source of Sonic hedgehog (Shh) in the adult forebrain, suggesting that Shh signaling is involved in neuron-astrocyte communication. Attenuation of Shh signaling in postnatal astrocytes by targeted removal of Smoothened, an obligate Shh coreceptor, resulted in upregulation of GFAP and cellular hypertrophy specifically in astrocyte populations regulated by Shh signaling. Collectively, our findings demonstrate a role for neuron-derived Shh in regulating specific populations of differentiated astrocytes.

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    • "The mosaic nature of the Cre recombination detects a relative ratio of expressing cells in a given population, rather than absolute numbers. In the normal adult mouse CNS, Gli1-CreERT2 mice have provided important insights into the role of Shh in self-renewal and multipotentiality of neural stem cells and in regulating astrocytic phenotypes (Ahn and Joyner, 2005; Garcia et al., 2010; Ihrie et al., 2011). Gli1-CreERT2 fate mapping of Shh pathway activation has not previously been studied in the context of CNS pathology. "
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    • "In the Emx1-Shh cKO, Gli1-nLacZ+ cells (likely due to the slow turnover of nLacZ) were also detected in a region slightly away from the VZ of the ventral hippocampus (arrows in Figure 4F 0 ), as in the control (arrows in Figure 4D 0 ). It has been reported that Gli1-nLacZ expression is affected by the functional copy number of Shh (Garcia et al., 2010). We reasoned that different copy numbers of Shh and Gli1-nLacZ would give us further insights into the formation of Gli1-nLacZ+ cell stream from the VZ of the ventral hippocampus and the de novo induction of Hh-responding cells in the forming DG. "
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    • "Shh expression has also been observed in both the juvenile and adult cerebral cortex (Charytoniuk et al., 2002) outside of known progenitor zones. Recently Shh expression has also been identified in cortical pyramidal neurons (Garcia et al., 2010). However, the function Shh in cortical neurons and the type of neurons expressing Shh remained unknown. "
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