Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine

Abstract

The transparency of the juvenile zebrafish and its genetic advantages make it an attractive model for study of cell turnover in the gut. BrdU labelling shows that the gut epithelium is renewed in essentially the same way as in mammals: the villi are lined with non-dividing differentiated cells, while cell division is confined to the intervillus pockets. New cells produced in the pockets take about 4 days to migrate out to the tips of the villi, where they die. We have generated monoclonal antibodies to identify the absorptive and secretory cells in the epithelium, and we have used these antibodies to examine the part that Delta-Notch signalling plays in producing the diversity of intestinal cell types. Several Notch receptors and ligands are expressed in the gut. In particular, the Notch ligand DeltaD (Delta1 in the mouse) is expressed in cells of the secretory lineage. In an aei mutant, where DeltaD is defective, secretory cells are overproduced. In mind bomb(mib), where all Delta-Notch signalling is believed to be blocked,almost all the cells in the 3-day gut epithelium adopt a secretory character. Thus, secretory differentiation appears to be the default in the absence of Notch activation, and lateral inhibition mediated by Delta-Notch signalling is required to generate a balanced mixture of absorptive and secretory cells. These findings demonstrate the central role of Notch signalling in the gut stem-cell system and establish the zebrafish as a model for study of the mechanisms controlling renewal of gut epithelium.

Direct regulation of intestinal fate by Notch

“…During the preparation of this manuscript, three other relevant reports were published (31)(32)(33). These studies support our conclusion that Notch regulates the secretory-absorptive cell fate decision in intestinal development.…”

Transcription factor onecut3 regulates intrahepatic biliary development in zebrafish

“…A comparable effect on biliary development of the oc3 knockdown was revealed by immunstainings with a monoclonal antibody (2F11; Crosnier et al, 2005) that detects biliary epithelial cell bodies and the proximal regions of the ducts arising from these cells. These stainings showed abnormal biliary epithelial cell morphology and a reduced ductal network .…”

“…Staining using 2F11 (Crosnier et al, 2005) was performed similarly, at a dilution of 1:1,000. Images were obtained using confocal microscopy of whole-mount livers.…”

Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis

“…Though Notch is best known for its role in lateral inhibition, activation of this pathway also promotes cell fate (Irvine 1999;Gaiano et al 2000;Grandbarbe et al 2003). Recent studies have shown that Notch signaling regulates a broad range of patterning processes during embryonic and postnatal development (Hitoshi et al 2002;Krebs et al 2003, Raya et al 2003Burns et al 2005;Crosnier et al 2005;Duncan et al 2005;Fre et al 2005;van Es et al 2005; for reviews, see Lai 2004;Yoon and Gaiano 2005).…”