Cdx2

Proximodistal organization

Gata4Represses Ileal gene program

Differentiated cellcompartment

Transient-amplifyingcompartment

Stem cell niche

Duodenum Jejunum Ileum Prox. colon Dist. colon

Caecum

Represses stomachgene program

M cell Enterocyte Goblet Endocrine

NeuroDElf3Cdx2+Hnf4

Elf3Spdef

Pax4/6Nkx2.2

RankL

Notch Dll1/4Absorptiveprogenitor

Secretory progenitor

Sox9Spdef

Math1 +WNT

Dama

ge

Damage

Paneth cellISCs(Lgr5+)

Spi-BNgn3?

?

Tuft

LRC(Lgr5+)

Hes1 Math1

Cell hierarchy and lineage specification

TIME

Restricted nichefor stem cells

Intestinal stem cells at the crypt base

Neutral competition inthe ISC niche

Paneth cellsLgr5+ stem cells

Symmetric stemcell divisions

Growth of surviving clones and extinctionof neighboring clones

Crypts inevitably drifttoward clonality

Anoikis

Nutrients

Cell amplification

Migration

PEYER’S PATCH

CRYPT

VILLUS

Lymphoid cellsLymphoid cells

EnterocytesNutrients absorption

Transient amplifying cellsProliferationLineage commitment

Paneth cellsInnate immune responseStem cell niche maintenance

Tuft cellsOpioids releaseProstanoids productionOther?

Goblet cellsMucus secretion

Enteroendocrine cellsHormone production

M cellsAntigen sampling

Intestinal stem cells (ISCs)Tissue renewal

Label retaining cells (LRCs)Paneth cell precursorsQuiescent cellsRegeneration of ISCs

The small intestine

WNTWNT

WNT

WNT

RSPO

β-cat

β-cat

NOTCHNOTCH-IC

DLL1/4

LRIG1

PA N E T HC E L L

I S C ( C B C )

ERBBProliferation

Inhibition of the secretory program: HES1Cell positioning: EPHB2

Silencing of cell-cycleinhibitors (p27kip, p57kip)

Repression of expression of Dll1/4

Proliferation, block differentiation: MYCRegulation of WNT signaling:

ZNRF3/RNF43, LGR5Cell positioning: EPHB2, EPHB3

Self-renewal: ASCL2

BMPRI

ZNRF3/RNF43

?

?

?

S T R O M A L C E L L

GREM

BMP

LGR4/5 FRIZZLEDLRP6

TCF

CSL

BMPRII

TGFα

EGF

Signaling in ISCs

SnapShot: The Intestinal CryptHans Clevers1 and Eduard Batlle2,31Hubrecht Institute, KNAW and University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, the Netherlands2Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain3Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

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DOCUMENT #28227 | VERSION 1.0.3