Organizing cell renewal in the intestine: stem cells, signals and combinatorial control

KEY POINTS * The epithelial lining of the intestine renews itself more rapidly than any other tissue in the vertebrate body, replacing the entire population of differentiated cells that

cover the intestinal villi every few days. * Stem cells and their transit-amplifying progeny reside in intervillus pockets (in the fetus or neonate) or crypts of Lieberkühn (in the adult),

and give rise to four classes of non-dividing differentiated cells — three secretory and one absorptive. * Transit-amplifying cells in the crypts probably become committed as secretory or

absorptive progenitors several cycles before they stop dividing. The secretory progenitors express mouse atonal homologue 1 (_Math1_), and no secretory cells are produced when _Math1_ is

defective. * Epithelial cells in each stem-cell region (crypt or pocket) produce a hedgehog signal that acts on the mesenchyme, evoking expression of bone morphogenetic protein (BMP). BMP

acts back on the epithelium to inhibit formation of ectopic stem-cell regions. * The stem-cell regions of epithelium maintain themselves by canonical Wnt signalling, apparently through an

auto-activating feedback loop. * When the canonical Wnt signalling pathway is blocked, proliferation fails and secretory cells are lacking; when the pathway is overactivated, proliferation

is excessive and tumours develop, containing a mixture of cell types (adenomatous polyps). * The proliferative epithelial cells in the crypts also interact with one another by Notch

signalling, mediating lateral inhibition. When the Notch signalling pathway is blocked, proliferation fails and all the crypt cells become secretory; when the pathway is overactivated,

proliferation continues but no secretory cells are produced. * Wnt and Notch signals collaborate to maintain intestinal stem cells: neither pathway on its own is sufficient. But Wnt pathway

activation can induce expression of Notch pathway components and so produce the collaborative effect. * Wnt signalling also regulates the expression of Eph/ephrins. Eph/ephrin signalling in

turn controls the migratory behaviour that keeps proliferative and differentiated cells segregated along the crypt–villus axis. * Wnt and Notch signals collaborate in a remarkably similar

way to maintain stem cells in the haemopoietic system and the CNS. But in some other tissues where both pathways are crucial, such as the epidermis, the rules of stem-cell maintenance are

different. ABSTRACT The lining of the intestine is renewed at an extraordinary rate, outpacing all other tissues in the vertebrate body. The renewal process is neatly organized in space, so

that the whole production line, from the ever-youthful stem cells to their dying, terminally differentiated progeny, is laid out to view in histological sections. A flurry of recent papers

has clarified the key regulatory signals and brought us to the point where we can begin to give a coherent account, for at least one tissue, of how these signals collaborate to organize the

architecture and behaviour of a stem-cell system. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CELLULAR AND MOLECULAR ARCHITECTURE OF THE INTESTINAL STEM CELL NICHE Article 03

September 2020 RETROGRADE MOVEMENTS DETERMINE EFFECTIVE STEM CELL NUMBERS IN THE INTESTINE Article 13 July 2022 CELL FATE SPECIFICATION AND DIFFERENTIATION IN THE ADULT MAMMALIAN INTESTINE

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Download references ACKNOWLEDGEMENTS We thank N. Wright and the anonymous referees for helpful comments, and Cancer Research UK for financial support. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Vertebrate Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK Cécile Crosnier, Despina Stamataki & 

Julian Lewis Authors * Cécile Crosnier View author publications You can also search for this author inPubMed Google Scholar * Despina Stamataki View author publications You can also search

for this author inPubMed Google Scholar * Julian Lewis View author publications You can also search for this author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing financial interests. RELATED LINKS RELATED LINKS DATABASES OMIM juvenile polyposis syndrome GLOSSARY * Niche The specific microenvironment that stem cells

inhabit. * Clonal analysis Analysis of the composition and distribution of the clones of cells that are descended from individual, heritably marked cells, in order to discover the fate of

these progenitors. * Pseudostratified Describes an epithelium that, because of the uneven positions of the cell nuclei, seems to contain several layers of cells (stratified) but is in fact

composed of a single one, in which all cells make contact with the basal surface. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Crosnier, C.,

Stamataki, D. & Lewis, J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. _Nat Rev Genet_ 7, 349–359 (2006). https://doi.org/10.1038/nrg1840

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