Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1452-6. Epub 2006 Jan 23.

Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice.

Author information

  • 1Department of Physiology and McKusick-Nathans Institute for Genetic Medicine, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5242.

Abstract

Trisomy 21 is the cause of Down [corrected] 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.

PMID:
16432181
[PubMed - indexed for MEDLINE]
PMCID:
PMC1360600
Free PMC Article

Images from this publication.See all images (3)Free text

Fig. 1.
Fig. 2.
Fig. 3.
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk