Playing Sonic Hedgehog in the Hippocampus

The developmental signaling protein sonic hedgehog (Shh) appears to play a significant role in regulating the proliferation of adult stem cells, according to a report in yesterday’s Nature Neuroscience.

Critical to the possibility of using stem cells to replace neurons in neurodegenerative disease is understanding the mechanisms that control the proliferation of stem cells and their differentiation into neurons (see related news item). Among the more important regulators of neural development uncovered to date are the hedgehog family of signaling molecules, including the one named after the video game character Sonic the hedgehog (Shh). However, Shh is also found in many areas of the adult nervous system, including the hippocampus. In the present study, David Schaffer and Karen Lai of the University of California at Berkeley, along with Brian Kaspar and Fred Gage of the Salk Institute in San Diego, California, sought to determine whether Shh plays a role in regulating the ongoing neurogenesis that replenishes the granule cells of the dentate gyrus in the adult hippocampus.

Although the researchers were not able to detect Shh itself in the hippocampus (a limitation of the available antibodies, the authors write), antibodies to the Shh receptor Patched revealed high hippocampal expression of the receptor in brain sections, as well as in neural progenitor cells isolated from the hippocampus. In culture, the addition of Shh to these stem cells stimulated cell proliferation. The cells generated by this means appear to retain their multipotency.

The researchers then moved their experiments into live animals. With the introduction of Shh cDNA to the rat hippocampus via a viral vector, cell proliferation increased 3.3-fold. Conversely, the direct injection of cyclopamine-an inhibitor of the hedgehog signaling pathway -into the hippocampus reduced hippocampal cell proliferation to half that of vehicle-injected animals.

The authors remind us of one caveat in the quest to harness adult stem cells to the task of replacing lost neurons, namely, the possibility that proliferation-promoting molecules will also promote tumor formation. Just as the proposed use of cylcopamine (or other hedgehog pathway inhibitors) to treat medulloblastoma might have a negative effective on normal hippocampal cell proliferation (with potential attendant cognitive side effects), the use of molecules that increase activity in the hedgehog pathway might favor the growth of such tumors.—Hakon Heimer

Comments

  1. The intrinsic signals that regulate the extent of adult neurogenesis are incompletely understood. In neurodegenerative diseases such as Alzheimer’s disease, neuronal dysfunction and loss underlie cognitive impairment. Understanding and perhaps exploiting nature’s own mechanisms to generate new and functional neurons may represent a future therapeutic opportunity. In this interesting new paper Lai et al. demonstrate that Sonic hedgehog (Shh) can markedly stimulate neurogenesis. Unlike Shh, its receptor Patched (Ptc) is expressed in the hippocampus, thus raising the possibility that neuronal projections may control the delivery of Shh.

    Using combined in vitro and in vivo methods the investigators show that Ssh can increase the apparent rate of neurogenesis from precursor cells. Whereas lineage representation does not appear altered by Shh, the total number of surviving cells is increased. Whether these precursor-derived post-mitotic derivatives become functionally integrated into neuronal circuits is not yet known.

    Two most interesting observations warrant mention. Firstly, Shh gene transfer into dentate gyrus (DG) can trigger excessive neurogenesis. This may have relevance to a gene-therapeutic repopulation of the damaged and neuron-depleted hippocampal formation. Secondly, the afferent projections from basal forebrain to hippocampus regulate DG neurogenesis, perhaps in an Shh-dependent manner. The authors speculate that inhibitory septohippocampal GABAergic neurons release Shh in an activity-dependent manner. Such demonstration would catalyze the search for compounds that mimic this process as they might be used to control neurogenesis in an anatomically directed manner.

    View all comments by Howard Federoff

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References

News Citations

  1. Turning Stem Cells into Motor Neurons

Further Reading

Papers

  1. Reilly JO, Karavanova ID, Williams KP, Mahanthappa NK, Allendoerfer KL. Cooperative effects of Sonic Hedgehog and NGF on basal forebrain cholinergic neurons. Mol Cell Neurosci. 2002 Jan;19(1):88-96. PubMed.
  2. Paganelli AR, Ocaña OH, Prat MI, Franco PG, López SL, Morelli L, Adamo AM, Riccomagno MM, Matsubara E, Shoji M, Affranchino JL, Castaño EM, Carrasco AE. The Alzheimer-related gene presenilin-1 facilitates sonic hedgehog expression in Xenopus primary neurogenesis. Mech Dev. 2001 Sep;107(1-2):119-31. PubMed.
  3. Tsuboi K, Shults CW. Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson's disease. Exp Neurol. 2002 Jan;173(1):95-104. PubMed.

Primary Papers

  1. Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci. 2003 Jan;6(1):21-7. PubMed.

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