The Hedgehog Pathway and Neurological Disorders

Abstract

The hedgehog pathway is a major regulator of embryonic development, and mutations that decrease its activity are known to be associated with severe defects in nervous system development. Recent evidence suggests hedgehog continues to function in adult tissue, normal as well as diseased, by regulating both cell proliferation and the production of growth and angiogenic factors. In the adult nervous system, this dual ability is especially important in regulating the behavior of neural stem and progenitor cells. This review summarizes information connecting hedgehog signaling and neural diseases, including neurodegenerative disorders and brain tumors, particularly medulloblastoma. We also describe the discovery and utility of small molecule agonists and antagonists of this pathway and their potential as novel types of therapeutics.

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

“…17,44 Apparently, similar mechanisms mediate reconstruction of adult tissues after damage because Hh pathway activation has been reported to occur during injury to various adult tissues. 45 The likelihood that Hh signaling normally exerts net trophic effects in injured adults, as it does in embryos, is further supported by evidence that injection of Hh ligands improves repair of infarcted myocardium and ischemic neuropathies. 21 However, appropriate constraint of Hh pathway activity is essential for good outcomes because excessive Hh signaling leads to developmental anomalies in embryos 46 and promotes the growth of many types of cancers, including hepatocellular carcinomas and cholangiocarcinomas, in adults.…”

REST In Good Times and Bad: Roles In Tumor Suppressor and Oncogenic Activities

“…Pathways regulating cerebellar development, such as Hedgehog and Wnt, have been found to be activated by genetic alterations during medulloblastoma tumorigenesis. [35][36][37][38][39][40][41][42][43][44] Both Hedgehog and Wnt are thought to regulate proliferation and differentiation of Roles In Tumor Suppressor and Oncogenic Activities Figure 3. Activation of REST target genes in committed myoblasts is sufficient to convert the myoblasts into a physiologically active neuronal phenotype.…”

Stabilization of Speckle-type POZ Protein (Spop) by Daz Interacting Protein 1 (Dzip1) Is Essential for Gli Turnover and the Proper Output of Hedgehog Signaling

“…In many cases Hh ligands function as morphogens to regulate cell fate determination in a multicellular target field or as mitogens to control cellular proliferation and survival. Understanding the many orchestrated events that transduce the Hh signal is of considerable interest, as perturbations to the Hh pathway lead to a variety of developmental disorders (1)(2)(3). In addition, a wide range of cancers are caused by unchecked Hh signaling (4 -6).…”