Sonic hedgehog controls stem cell behavior in the postnatal and adult brain

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 forebrain's 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.

[1]  J. García-Verdugo,et al.  Noggin Antagonizes BMP Signaling to Create a Niche for Adult Neurogenesis , 2000, Neuron.

[2]  S. Temple,et al.  LeX/ssea-1 Is Expressed by Adult Mouse CNS Stem Cells, Identifying Them as Nonependymal , 2002, Neuron.

[3]  A. Joyner,et al.  Gli1 can rescue the in vivo function of Gli2. , 2001, Development.

[4]  S. Deventer,et al.  Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. , 2001, Gastroenterology.

[5]  H. Markram,et al.  Anatomical, physiological, molecular and circuit properties of nest basket cells in the developing somatosensory cortex. , 2002, Cerebral cortex.

[6]  A. Álvarez-Buylla,et al.  Stem cells in the adult mammalian central nervous system , 1999, Current Opinion in Neurobiology.

[7]  V. Palma,et al.  Hedgehog–GLI signaling and the growth of the brain , 2002, Nature Reviews Neuroscience.

[8]  F. Gage,et al.  Adult neurogenesis and neural stem cells of the central nervous system in mammals , 2002, Journal of neuroscience research.

[9]  C. Lois,et al.  Long-distance neuronal migration in the adult mammalian brain. , 1994, Science.

[10]  V. Wallace.  Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum , 1999, Current Biology.

[11]  R. McKay.  Stem cell biology and neurodegenerative disease. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[12]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[13]  A. Ruiz i Altaba,et al.  Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. , 1997, Development.

[14]  H. Markram,et al.  Correlation maps allow neuronal electrical properties to be predicted from single-cell gene expression profiles in rat neocortex. , 2004, Cerebral cortex.

[15]  D. van der Kooy,et al.  Adult Rodent Neurogenic Regions: The Ventricular Subependyma Contains Neural Stem Cells, But the Dentate Gyrus Contains Restricted Progenitors , 2002, The Journal of Neuroscience.

[16]  A. Ruiz i Altaba,et al.  Sonic hedgehog regulates the growth and patterning of the cerebellum. , 1999, Development.

[17]  Thomas M Jessell,et al.  Development The decade of the developing brain , 2000, Current Opinion in Neurobiology.

[18]  Johan Ericson,et al.  Two Critical Periods of Sonic Hedgehog Signaling Required for the Specification of Motor Neuron Identity , 1996, Cell.

[19]  A. Prochiantz,et al.  Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone , 2004, Development.

[20]  T. Jessell,et al.  Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm , 1995, Cell.

[21]  H. Weiner,et al.  The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. , 2001, Development.

[22]  Andrew P. McMahon,et al.  Sonic Hedgehog Is Required for Progenitor Cell Maintenance in Telencephalic Stem Cell Niches , 2003, Neuron.

[23]  C. Dulac.  Cloning of genes from single neurons. , 1998, Current topics in developmental biology.

[24]  E. Dzierzak,et al.  Expression of the Ly-6E.1 (Sca-1) transgene in adult hematopoietic stem cells and the developing mouse embryo. , 1997, Development.

[25]  C. Dulac.  14 Cloning of Genes from Single Neurons , 1997 .

[26]  P. Hantraye,et al.  Intrastriatal sonic hedgehog injection increases Patched transcript levels in the adult rat subventricular zone , 2002, The European journal of neuroscience.

[27]  A. R. I. Altaba.  Combinatorial Gli Gene Function in Floor Plate and Neuronal Inductions by Sonic Hedgehog , 1998 .

[28]  Daniel A. Lim,et al.  Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain , 1999, Cell.

[29]  A. Joyner,et al.  Gli 1 can rescue the in vivo function of Gli 2 , 2022 .

[30]  R. Kapur,et al.  The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. , 1998, Development.

[31]  Charles Duyckaerts,et al.  Dopamine depletion impairs precursor cell proliferation in Parkinson disease , 2004, Nature Neuroscience.

[32]  M. Ruat,et al.  Discrete localizations of hedgehog signalling components in the developing and adult rat nervous system , 1999, The European journal of neuroscience.

[33]  A. Gurney,et al.  Control of Cell Pattern in the Neural Tube by the Zinc Finger Transcription Factor and Oncogene Gli-1 , 1997, Neuron.

[34]  Arturo Alvarez-Buylla,et al.  EGF Converts Transit-Amplifying Neurogenic Precursors in the Adult Brain into Multipotent Stem Cells , 2002, Neuron.

[35]  A. Álvarez-Buylla,et al.  Identification of neural stem cells in the adult vertebrate brain , 2002, Brain Research Bulletin.

[36]  Jonas Frisén,et al.  Identification of a Neural Stem Cell in the Adult Mammalian Central Nervous System , 1999, Cell.

[37]  M. Scott,et al.  Control of Neuronal Precursor Proliferation in the Cerebellum by Sonic Hedgehog , 1999, Neuron.

[38]  Alan Carleton,et al.  Becoming a new neuron in the adult olfactory bulb , 2003, Nature Neuroscience.

[39]  J. García-Verdugo,et al.  Astrocytes Give Rise to New Neurons in the Adult Mammalian Hippocampus , 2001, The Journal of Neuroscience.

[40]  A. Álvarez-Buylla,et al.  Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[41]  P. Beachy,et al.  Teratogen-mediated inhibition of target tissue response to Shh signaling. , 1998, Science.

[42]  V. Palma,et al.  Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex , 2003, Development.

[43]  S. Kunes,et al.  Hedgehog, Transmitted along Retinal Axons, Triggers Neurogenesis in the Developing Visual Centers of the Drosophila Brain , 1996, Cell.

[44]  Fred H. Gage,et al.  Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo , 2003, Nature Neuroscience.