spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online August 21, 2009
doi: 10.1242/10.1242/dev.031302

Development 136, 3195-3203 (2009)
Published by The Company of Biologists 2009
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Druckenbrod, N. R.
Right arrow Articles by Epstein, M. L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Druckenbrod, N. R.
Right arrow Articles by Epstein, M. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Age-dependent changes in the gut environment restrict the invasion of the hindgut by enteric neural progenitors

Noah R. Druckenbrod1,2 and Miles L. Epstein1,*

1 Department of Anatomy and Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
2 Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.

* Author for correspondence (mepstein{at}wisc.edu)

Accepted 22 July 2009

The enteric nervous system (ENS) develops from neural crest cells (NCCs) that enter the foregut and hindgut to become enteric neural-crest-derived cells (ENCCs). When these cells of neural crest origin fail to colonize the terminal hindgut, this aganglionic region becomes non-functional and results in a condition in humans known as Hirschsprung's disease (HSCR). One of the genes associated with HSCR is endothelin receptor type B (Ednrb). To study the development of colonic aganglionosis we have utilized a novel knockout mouse (Ednrbflex3/flex3), in which the expression of a null Ednrb allele and YFP is confined to NCCs. We have identified two primary cellular defects related to defective EDNRB signaling. First, ENCC advance in Ednrbflex3/flex3 embryos is delayed shortly after NCCs enter the gut. Apart from this early delay, Ednrbflex3/flex3 ENCCs advance normally until reaching the proximal colon. Second, as Ednrbflex3/flex3 ENCCs reach the colon at E14.5, they display migratory defects, including altered trajectories and reduced speed, that are not dependent on proliferation or differentiation. We constructed grafts to test the ability of donor ENCCs to invade a recipient piece of aganglionic colon. Our results indicate that the age of the recipient, and not the age or genotype of donor ENCCs, determines whether the colon is invaded. We identify changes in laminin expression that are associated with the failure of ENCCs to invade recipient tissue. Together, our data suggest that a defect in pre-enteric Ednrbflex3/flex3 NCCs results in delayed colonic arrival, which, due to environment changes in the colon, is sufficient to cause aganglionosis.

Key words: Hirschsprung's disease, Endothelin receptor B, Multicellular invasion, Neural crest cells, Time-lapse microscopy, Tissue graft, Cre-lox, Colon, Mouse


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?




© The Company of Biologists Ltd 2009