Sonic hedgehog (Shh) signaling controls many aspects of ontogeny, orchestrating congruent growth and patterning. During brain development, Shh regulates early ventral patterning while later on it is critical for the regulation of precursor proliferation in the dorsal brain, namely in the neocortex, tectum and cerebellum. We have recently shown that Shh also controls the behavior of cells with stem cell properties in the mouse embryonic neocortex, and additional studies have implicated it in the control of cell proliferation in the adult ventral forebrain and in the hippocampus. However, it remains unclear whether it regulates adult stem cell lineages in an equivalent manner. Similarly, it is not known which cells respond to Shh signaling in stem cell niches. Here we demonstrate that Shh is required for cell proliferation in the mouse forebrain9s subventricular zone (SVZ) stem cell niche and for the production of new olfactory interneurons in vivo. We identify two populations of Gli1⁺ Shh signaling responding cells: GFAP⁺ SVZ stem cells and GFAP^- precursors. Consistently, we show that Shh regulates the self-renewal of neurosphere-forming stem cells and that it modulates proliferation of SVZ lineages by acting as a mitogen in cooperation with epidermal growth factor (EGF). Together, our data demonstrate a critical and conserved role of Shh signaling in the regulation of stem cell lineages in the adult mammalian brain, highlight the subventricular stem cell astrocytes and their more abundant derived precursors as in vivo targets of Shh signaling, and demonstrate the requirement for Shh signaling in postnatal and adult neurogenesis.

Prostate cancer is the most common solid tumor in men, and it shares with all cancers the hallmark of elevated, nonhomeostatic cell proliferation. Here we have tested the hypothesis that the SONIC HEDGEHOG (SHH)–GLI signaling pathway is implicated in prostate cancer. We report expression of SHH–GLI pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. Blocking the pathway with cyclopamine or anti-SHH antibodies inhibits the proliferation of GLI1 ⁺ / PSA ⁺ primary prostate tumor cultures. Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth. In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through GLI1 RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells. Our data demonstrate the dependence of prostate cancer on SHH–GLI function and suggest a novel therapeutic approach.

The two members of the atypical protein kinase C (aPKC) subfamily of isozymes (ζPKC and λ/ιPKC) are involved in the control of nuclear factor κB (NF‐κB) through IKKβ activation. Here we show that the previously described aPKC‐binding protein, p62, selectively interacts with RIP but not with TRAF2 in vitro and in vivo . p62 bridges the aPKCs to RIP, whereas the aPKCs link IKKβ to p62. In this way, a signaling cascade of interactions is established from the TNF‐R1 involving TRADD/RIP/p62/aPKCs/IKKβ. These observations define a novel pathway for the activation of NF‐κB involving the aPKCs and p62. Consistent with this model, the expression of a dominant‐negative mutant λ/ιPKC impairs RIP‐stimulated NF‐κB activation. In addition, the expression of either an N‐terminal aPKC‐binding domain of p62, or its C‐terminal RIP‐binding region are sufficient to block NF‐κB activation. Furthermore, transfection of an antisense construct of p62 severely abrogates NF‐κB activation. Together, these results demonstrate that the interaction of p62 with RIP serves to link the atypical PKCs to the activation of NF‐κB by the TNFα signaling pathway.