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MEDICAL SCIENCES
Defective cerebellar response to mitogenic Hedgehog signaling in Down's syndrome mice
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*Department of Physiology and McKusick–Nathans Institute for Genetic Medicine, Howard Hughes Medical Institute, and Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
Contributed by Philip A. Beachy, December 13, 2005
Trisomy 21 is the cause of Down's syndrome (DS) which is characterized by a number of phenotypes, including a brain which is small and hypocellular compared to that of euploid individuals. The cerebellum is disproportionately reduced. Ts65Dn mice are trisomic for orthologs of about half of the genes on human chromosome 21 and provide a genetic model for DS. These mice display a number of developmental anomalies analogous to those in DS, including a small cerebellum with a significantly decreased number of both granule and Purkinje cell neurons. Here we trace the origin of the granule cell deficit to precursors in early postnatal development, which show a substantially reduced mitogenic response to Hedgehog protein signaling. Purified cultures of trisomic granule cell precursors show a reduced but dose-dependent response to the Sonic hedgehog protein signal in vitro, demonstrating that this is a cell-autonomous deficit. Systemic treatment of newborn trisomic mice with a small molecule agonist of Hedgehog pathway activity increases mitosis and restores granule cell precursor populations in vivo. These results demonstrate a basis for and a potential therapeutic approach to a fundamental aspect of CNS pathology in DS.
aneuploidy | neuronal deficit | sonic hedgehog | trisomy 21
Conflict of interest statement: P.A.B. is a paid consultant for and P.A.B. and Johns Hopkins University hold stock in Curis, Inc.
Abbreviations: chr, chromosome; DS, Down's syndrome; IGL, internal granule layer; GCP, granule cell precursor; EGL, external germinal layer; Pn, postnatal day n; Shh, Sonic hedgehog; Hh, hedgehog.
R.J.R. and L.L.B. contributed equally to this work.
Present address: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
¶ To whom correspondence may be addressed. E-mail: rreeves{at}jhmi.edu or pbeachy{at}jhmi.edu.
© 2006 by The National Academy of Sciences of the USA
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