title: Dendrosomatic Sonic Hedgehog Signaling in Hippocampal Neurons Regulates Axon Elongation.
abstract: The presence of Sonic Hedgehog (Shh) and its signaling components in the neurons of the hippocampus raises a question about what role the Shh signaling pathway may play in these neurons. We show here that activation of the Shh signaling pathway stimulates axon elongation in rat hippocampal neurons. This Shh-induced effect depends on the pathway transducer Smoothened (Smo) and the transcription factor Gli1. The axon itself does not respond directly to Shh; instead, the Shh signal transduction originates from the somatodendritic region of the neurons and occurs in neurons with and without detectable primary cilia. Upon Shh stimulation, Smo localization to dendrites increases significantly. Shh pathway activation results in increased levels of profilin1 (Pfn1), an actin-binding protein. Mutations in Pfn1's actin-binding sites or reduction of Pfn1 eliminate the Shh-induced axon elongation. These findings indicate that Shh can regulate axon growth, which may be critical for development of hippocampal neurons.
  
  
  CONCLUSIONS
  Although numerous signaling mechanisms have been identified that act directly on axons to regulate their outgrowth, it is not known whether signals transduced in dendrites may also affect axon outgrowth. We describe here a transcellular signaling pathway in embryonic hippocampal neurons in which activation of Sonic Hedgehog (Shh) receptors in dendrites stimulates axon growth. The pathway involves the dendritic-membrane-associated Shh signal transducer Smoothened (Smo) and the transcription factor Gli, which induces the expression of the gene encoding the actin-binding protein profilin 1. Our findings suggest scenarios in which stimulation of Shh in dendrites results in accelerated outgrowth of the axon, which therefore reaches its presumptive postsynaptic target cell more quickly. By this mechanism, Shh may play critical roles in the development of hippocampal neuronal circuits.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging-National Institutes of Health, Baltimore, Maryland 21224, yaopa@grc.nia.nih.gov.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Yao
authors.affiliation: Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders (NIDCD)-National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development-National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ott
authors.affiliation: Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders (NIDCD)-National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Ya-Xian
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development-National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lippincott-Schwartz
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging-National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D051304:Profilins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000072086:Smoothened Receptor; D013997:Time Factors; D000071676:Zinc Finger Protein GLI1
chemical_list: C498521:Gli1 protein, rat; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C495740:Pfn1 protein, rat; D051304:Profilins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C498555:Smo protein, rat; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1
keywords: Smoothened; Sonic Hedgehog; axon; hippocampal neuron; primary cilium; profilin 1