{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:19:14Z","timestamp":1791317954819,"version":"4.3.1"},"reference-count":34,"publisher":"The Company of Biologists","issue":"22","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,11,15]]},"abstract":"<jats:p>The cerebellum consists of a highly organized set of folia that are largely generated postnatally during expansion of the granule cell precursor (GCP)pool. Since the secreted factor sonic hedgehog (Shh) is expressed in Purkinje cells and functions as a GCP mitogen in vitro, it is possible that Shh influences foliation during cerebellum development by regulating the position and\/or size of lobes. We studied how Shh and its transcriptional mediators,the Gli proteins, regulate GCP proliferation in vivo, and tested whether they influence foliation. We demonstrate that Shh expression correlates spatially and temporally with foliation. Expression of the Shh target gene Gli1 is also highest in the anterior medial cerebellum, but is restricted to proliferating GCPs and Bergmann glia. By contrast, Gli2is expressed uniformly in all cells in the developing cerebellum except Purkinje cells and Gli3 is broadly expressed along the anteroposterior axis. Whereas Gli mutants have a normal cerebellum, Gli2 mutants have greatly reduced foliation at birth and a decrease in GCPs. In a complementary study using transgenic mice, we show that overexpressing Shh in the normal domain does not grossly alter the basic foliation pattern, but does lead to prolonged proliferation of GCPs and an increase in the overall size of the cerebellum. Taken together, these studies demonstrate that positive Shh signaling through Gli2 is required to generate a sufficient number of GCPs for proper lobe growth.<\/jats:p>","DOI":"10.1242\/dev.01438","type":"journal-article","created":{"date-parts":[[2004,10,21]],"date-time":"2004-10-21T00:13:29Z","timestamp":1098317609000},"page":"5581-5590","source":"Crossref","is-referenced-by-count":266,"title":["Spatial pattern of sonic hedgehog signaling through<i>Gli<\/i>genes during cerebellum development"],"prefix":"10.1242","volume":"131","author":[{"given":"JoMichelle D.","family":"Corrales","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, NY 10016,USA"},{"name":"Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina L.","family":"Rocco","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, NY 10016,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Blaess","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, NY 10016,USA"},{"name":"Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxia","family":"Guo","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, NY 10016,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra L.","family":"Joyner","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, NY 10016,USA"},{"name":"Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA"},{"name":"Department of Physiology and Neuroscience, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042612040924800_REF1","unstructured":"Altman, J. and Bayer, S. A. (1997). Development of the Cerebellar System: In relation to its Evolution,Structure, and Functions. New York, NY: CRC Press."},{"key":"2021042612040924800_REF2","unstructured":"Bai, C. B. and Joyner, A. L. (2001). Gli1 can rescue the in vivo function of Gli2. Development128,5161-5172."},{"key":"2021042612040924800_REF3","unstructured":"Bai, C. B., Auerbach, W., Lee, J. S., Stephen, D. and Joyner, A. L. (2002). Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development129,4753-4761."},{"key":"2021042612040924800_REF4","doi-asserted-by":"crossref","unstructured":"Bai, C. B., Stephen, D. and Joyner, A. L.(2004). All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell6,103-115.","DOI":"10.1016\/S1534-5807(03)00394-0"},{"key":"2021042612040924800_REF5","unstructured":"Caddy, K. W. and Biscoe, T. J. (1979). Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. Philos. Trans. R. Soc. Lond., B, Biol. Sci.287,167-201."},{"key":"2021042612040924800_REF6","doi-asserted-by":"crossref","unstructured":"Chiang, C., Litingtung, Y., Lee, E., Young, K. E., Corden, J. L., Westphal, H. and Beachy, P. A. (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature383,407-413.","DOI":"10.1038\/383407a0"},{"key":"2021042612040924800_REF7","doi-asserted-by":"crossref","unstructured":"Dahmane, N. and Ruiz i Altaba, A. (1999). Sonic hedgehog regulates the growth and patterning of the cerebellum. Development126,3089-3100.","DOI":"10.1242\/dev.126.14.3089"},{"key":"2021042612040924800_REF8","unstructured":"Herrup, K. (1983). Role of staggerer gene in determining cell number in cerebellar cortex. I. Granule cell death is an indirect consequence of staggerer gene action. Brain Res.313,267-274."},{"key":"2021042612040924800_REF9","doi-asserted-by":"crossref","unstructured":"Herrup, K. and Wilczynski, S. L. (1982). Cerebellar cell degeneration in the leaner mutant mouse. Neuroscience7,2185-2196.","DOI":"10.1016\/0306-4522(82)90129-4"},{"key":"2021042612040924800_REF10","doi-asserted-by":"crossref","unstructured":"Ingham, P. W. and McMahon, A. P. (2001). Hedgehog signaling in animal development: paradigms and principles. Genes Dev.15,3059-3087.","DOI":"10.1101\/gad.938601"},{"key":"2021042612040924800_REF11","doi-asserted-by":"crossref","unstructured":"Jacob, J. and Briscoe, J. (2003). Gli proteins and the control of spinal-cord patterning. EMBO Rep.4, 761-765.","DOI":"10.1038\/sj.embor.embor896"},{"key":"2021042612040924800_REF12","doi-asserted-by":"crossref","unstructured":"Kenney, A. M., Cole, M. D. and Rowitch, D. H.(2003). Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development130,15-28.","DOI":"10.1242\/dev.00182"},{"key":"2021042612040924800_REF13","doi-asserted-by":"crossref","unstructured":"Knoepfler, P. S., Cheng, P. F. and Eisenman, R. N.(2002). N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev.16,2699-2712.","DOI":"10.1101\/gad.1021202"},{"key":"2021042612040924800_REF14","doi-asserted-by":"crossref","unstructured":"Litingtung, Y., Dahn, R. D., Li, Y., Fallon, J. F. and Chiang,C. (2002). Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature418,979-983.","DOI":"10.1038\/nature01033"},{"key":"2021042612040924800_REF15","doi-asserted-by":"crossref","unstructured":"McAndrew, P. E., Frostholm, A., Evans, J. E., Zdilar, D.,Goldowitz, D., Chiu, I. M., Burghes, A. H. and Rotter, A.(1998). Novel receptor protein tyrosine phosphatase (RPTPrho) and acidic fibroblast growth factor (FGF-1) transcripts delineate a rostrocaudal boundary in the granule cell layer of the murine cerebellar cortex. J. Comp. Neurol.391,444-455.","DOI":"10.1002\/(SICI)1096-9861(19980222)391:4<444::AID-CNE3>3.0.CO;2-0"},{"key":"2021042612040924800_REF16","doi-asserted-by":"crossref","unstructured":"Millen, K. J., Hui, C. C. and Joyner, A. L.(1995). A role for En-2 and other murine homologues of Drosophila segment polarity genes in regulating positional information in the developing cerebellum. Development121,3935-3945.","DOI":"10.1242\/dev.121.12.3935"},{"key":"2021042612040924800_REF17","doi-asserted-by":"crossref","unstructured":"Miyazawa, K., Himi, T., Garcia, V., Yamagishi, H., Sato, S. and Ishizaki, Y. (2000). A role for p27\/Kip1 in the control of cerebellar granule cell precursor proliferation. J. Neurosci.20,5756-5763.","DOI":"10.1523\/JNEUROSCI.20-15-05756.2000"},{"key":"2021042612040924800_REF18","doi-asserted-by":"crossref","unstructured":"Mo, R., Freer, A. M., Zinyk, D. L., Crackower, M. A., Michaud,J., Heng, H. H., Chik, K. W., Shi, X. M., Tsui, L. C., Cheng, S. H. et al. (1997). Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development124,113-123.","DOI":"10.1242\/dev.124.1.113"},{"key":"2021042612040924800_REF19","doi-asserted-by":"crossref","unstructured":"Napieralski, J. A. and Eisenman, L. M. (1993). Developmental analysis of the external granular layer in the meander tail mutant mouse: do cerebellar microneurons have independent progenitors?Dev. Dyn.197,244-254.","DOI":"10.1002\/aja.1001970403"},{"key":"2021042612040924800_REF20","doi-asserted-by":"crossref","unstructured":"Palma, V. and Ruiz i Altaba, A. (2004). Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development131,337-345.","DOI":"10.1242\/dev.00930"},{"key":"2021042612040924800_REF21","doi-asserted-by":"crossref","unstructured":"Park, H. L., Bai, C., Platt, K. A., Matise, M. P., Beeghly, A.,Hui, C. C., Nakashima, M. and Joyner, A. L. (2000). Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development127,1593-1605.","DOI":"10.1242\/dev.127.8.1593"},{"key":"2021042612040924800_REF22","doi-asserted-by":"crossref","unstructured":"Persson, M., Stamataki, D., te Welscher, P., Andersson, E.,Bose, J., Ruther, U., Ericson, J. and Briscoe, J.(2002). Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Genes Dev.16,2865-2878.","DOI":"10.1101\/gad.243402"},{"key":"2021042612040924800_REF23","doi-asserted-by":"crossref","unstructured":"Riccomagno, M. M., Martinu, L., Mulheisen, M., Wu, D. K. and Epstein, D. J. (2002). Specification of the mammalian cochlea is dependent on Sonic hedgehog. Genes Dev.16,2365-2378.","DOI":"10.1101\/gad.1013302"},{"key":"2021042612040924800_REF24","doi-asserted-by":"crossref","unstructured":"Ross, M. E., Fletcher, C., Mason, C. A., Hatten, M. E. and Heintz, N. (1990). Meander tail reveals a discrete developmental unit in the mouse cerebellum. Proc. Natl. Acad. Sci. USA87,4189-4192.","DOI":"10.1073\/pnas.87.11.4189"},{"key":"2021042612040924800_REF25","doi-asserted-by":"crossref","unstructured":"Sidman, R. L., Lane, P. W. and Dickie, M. M.(1962). Staggerer, a new mutation in the mouse affecting the cerebellum. Science137,610-612.","DOI":"10.1126\/science.137.3530.610"},{"key":"2021042612040924800_REF26","doi-asserted-by":"crossref","unstructured":"Smeyne, R. J., Chu, T., Lewin, A., Bian, F., Crisman, S.,Kunsch, C., Lira, S. A. and Oberdick, J. (1995). Local control of granule cell generation by cerebellar Purkinje cells. Mol. Cell. Neurosci.6,230-251.","DOI":"10.1006\/mcne.1995.1019"},{"key":"2021042612040924800_REF27","doi-asserted-by":"crossref","unstructured":"te Welscher, P., Zuniga, A., Kuijper, S., Drenth, T., Goedemans,H. J., Meijlink, F. and Zeller, R. (2002). Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science298,827-830.","DOI":"10.1126\/science.1075620"},{"key":"2021042612040924800_REF28","doi-asserted-by":"crossref","unstructured":"Wallace, V. A. (1999). Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr. Biol.9, 445-448.","DOI":"10.1016\/S0960-9822(99)80195-X"},{"key":"2021042612040924800_REF29","doi-asserted-by":"crossref","unstructured":"Wang, B., Fallon, J. F. and Beachy, P. A.(2000). Hedgehog-regulated processing of Gli3 produces an anterior\/posterior repressor gradient in the developing vertebrate limb. Cell100,423-434.","DOI":"10.1016\/S0092-8674(00)80678-9"},{"key":"2021042612040924800_REF30","doi-asserted-by":"crossref","unstructured":"Wang, V. Y. and Zoghbi, H. Y. (2001). Genetic regulation of cerebellar development. Nat. Rev. Neurosci.2,484-491.","DOI":"10.1038\/35081558"},{"key":"2021042612040924800_REF31","doi-asserted-by":"crossref","unstructured":"Wechsler-Reya, R. J. (2001). Caught in the matrix: how vitronectin controls neuronal differentiation. Trends Neurosci.24,680-682.","DOI":"10.1016\/S0166-2236(00)02058-0"},{"key":"2021042612040924800_REF32","doi-asserted-by":"crossref","unstructured":"Wechsler-Reya, R. J. and Scott, M. P. (1999). Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron22,103-114.","DOI":"10.1016\/S0896-6273(00)80682-0"},{"key":"2021042612040924800_REF33","unstructured":"Weiner, H. L., Bakst, R., Hurlbert, M. S., Ruggiero, J., Ahn,E., Lee, W. S., Stephen, D., Zagzag, D., Joyner, A. L. and Turnbull, D. H. (2002). Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1. Cancer Res.62,6385-6389."},{"key":"2021042612040924800_REF34","unstructured":"Wetts, R. and Herrup, K. (1982). Interaction of granule, Purkinje and inferior olivary neurons in lurcher chimaeric mice. I. Qualitative studies. J. Embryol. Exp. 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