How: the long and short of intestinal stem cells

Qi J, Dominado N, Savva E, Casagranda F, Siddall NA and Hime GR

Department of Anatomy and Neuroscience, University of Melbourne, Parkville 3010, Australia.

Intestinal stem cells play a key role in maintaining the intestinal environment. Multiple signaling pathways regulate replication and differentiation of intestinal stem cells (ISCs). The midgut epithelium of Drosophila melanogaster is comprised of similar cell types to the vertebrate intestinal epithelium and has served as a model for identification of genes that regulate epithelial biology. We have recently used Drosophila to show that an RNA-binding protein, known as HOW (Held-out wings), is also involved in regulating ISCs. HOW can be found as 2 major isoforms; long and short proteins named HOW(L) and How(S) respectively. HOW(L) and HOW(S) have been shown to have opposing roles in regulation of tendon cell differentiation in the wings of the fly. Flies with this mutation have their wings perpendicular to their body which gave rise to the name, ’held- out wings’. The vertebrate ortholog of HOW is known as QKI (Quaking) and has been associated with regulation of colorectal cancer cell differentiation. The QKI gene also produces multiple isoforms; 2 of which are very similar to HOW(S) and HOW(L). Despite research showing that HOW is present in intestinal stem cells, little research has been conducted investigating its role and its targets. Complete loss of HOW function in the midgut results in a decrease in ISC number. Ectopic expression of HOW(L) results in an ISC increase and a corresponding decrease in the proportion of differentiated enterocytes. I aim to determine whether HOW(L) and HOW(S) have their own individual roles in intestinal stem cell maintenance or have redundant functions.