Intestinal differentiation in zebrafish requires Cdx1b, a functional equivalent of mammalian Cdx2.
OBJECTIVE
The ParaHox transcription factor Cdx2 is an essential determinant of intestinal phenotype in mammals throughout development, influencing gut function, homeostasis, and epithelial barrier integrity. Cdx2 expression demarcates the zones of intestinal stem cell proliferation in the adult gut, with deregulated expression implicated in intestinal metaplasia and cancer. However, in vivo analysis of these prospective roles has been limited because inactivation of Cdx2 in mice leads to preimplantation embryonic lethality. We used the zebrafish, a valuable model for studying gut development, to generate a system to further understanding of the role of Cdx2 in normal intestinal function and in disease states.


METHODS
We isolated and characterized the zebrafish cdx1b ortholog and analyzed its function by antisense morpholino gene knockdown.


RESULTS
We showed that zebrafish Cdx1b replaces the role of Cdx2 in gut development. Evolutionary studies have indicated that the zebrafish cdx2 loci were lost following the genome-wide duplication event that occurred in teleosts. Zebrafish Cdx1b is expressed exclusively in the developing intestine during late embryogenesis and regulates intestinal cell proliferation and terminal differentiation.


CONCLUSIONS
This work established an in vivo system to explore further the activity of Cdx2 in the gut and its impact on processes such as inflammation and cancer.
Flores
Maria Vega C
MV
Department of Molecular Medicine & Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
Hall
Chris J
CJ
Davidson
Alan J
AJ
Singh
Primal P
PP
Mahagaonkar
Alhad A
AA
Zon
Leonard I
LI
Crosier
Kathryn E
KE
Crosier
Philip S
PS
D000818:Animals; D017209:Apoptosis; D000071616:CDX2 Transcription Factor; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics*; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000196:embryology / Q000378:metabolism; D007422:Intestines / Q000196:embryology*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D000071616:CDX2 Transcription Factor; C529211:Cdx1b protein, zebrafish; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D004247:DNA