PerspectiveDevelopment

Epithelial Cell Differentiation--a Mather of Choice

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Science  07 Dec 2001:
Vol. 294, Issue 5549, pp. 2115-2116
DOI: 10.1126/science.1067751

The gastrointestinal tract endoderm differentiates into specialized epithelial cells that perform digestive, absorptive, protective, and endocrine tasks. These cells have a relatively short life-span and must be continuously replaced from a pool of progenitor cells. It is still unclear why a progenitor cell makes a “choice” to leave the progenitor pool and to adopt a specific cell fate. An initial decision in epithelial lineage determination involves the Notch signaling pathway, yet subsequent choices and the downstream targets of this pathway have yet to be completely identified. On page 2155 of this issue, Yang et al. (1) provide evidence that Math1, a basic helix-loop-helix transcription factor, is a “pro-choice” determinant of epithelial cell commitment, and is a downstream target of the Notch pathway.

The intestinal epithelium is thrown into fingerlike folds called villi, which are separated from each other by troughs called crypts (see the figure). The differentiated epithelial cells at the tips of the villi are replaced every few days by progenitor stem cells that dwell in the crypts and move up the villi as they differentiate (2). In the crypts, the progenitor stem cells succumb to lineage determination and eventually give rise to four types of differentiated gut epithelial cells—enterocytes, Paneth cells, goblet cells, and enteroendocrine cells. These initial differentiation events are affected by the position of the epithelial cell along the crypt-to-villus axis and by its interactions with neighboring cells (3). It is not clear how progenitor stem cells in the crypt become lineage restricted. But, just before they leave the crypt, these lineage-restricted undifferentiated cells undergo a switch, withdraw from the cell cycle, and begin to express specialized proteins. The differentiated cells then migrate up the villi and, after reaching the top, undergo apoptosis, thereby maintaining homeostasis of the intestinal epithelium. Coordination between proliferation, differentiation, and apoptosis requires the well-timed interplay of different signaling pathways.

A gut instinct about cell fate.

(A) Low-power 4-μm section of adult murine small intestine. Precursor cells (brown) are stained for cyclin PCNA (proliferating cell nuclear antigen); enterocytes (red) express intestinal alkaline phosphatase (IAP); goblet cells (blue) secrete mucins. Inset shows high-power image of small intestine enterocytes and goblet cells. (B) Math1, a component of the Notch signaling pathway, influences intestinal epithelial cell fate decisions. In crypt progenitor stem cells that express high levels of Notch, the Hes1 transcription factor is switched on and the expression of Math1 and of other “prosecretory” genes is blocked. The result is that the precursor cells become enterocytes. In cells expressing low amounts of Notch, levels of Delta are high, production of Hes1 is blocked, and Math1 expression is induced. Production of the Math1 helix-loop-helix transcription factor allows precursor cells to make a choice: whether to become goblet cells, Paneth cells, or enteroendocrine cells (Vi, villus; Cr, crypt).

The Notch pathway specifies cell fate through feedback amplification of relative differences in cellular levels of Notch and its ligand Delta (4). This results in subsets of cells that produce large amounts of Notch. These cells induce expression of transcription factors, such as Hes1 (5). Hes1is a transcriptional repressor, and therefore cells that express the Hes1 gene remain precursor cells (6). Yang et al. further dissect this pathway by showing that Math1 is a downstream target of Hes1 and controls the initial choice of fate made by crypt progenitor stem cells (see the figure).

Math1 is expressed in developing and mature mouse intestinal epithelium. Yang and colleagues used reporter constructs to show that Math1-deficient mice have increased expression of the reporter gene in crypt cells. However, they lack goblet, Paneth, and enteroendocrine cells, and show no increase in the programmed cell death of cells at the tips of the villi. These findings suggest that Math1 is involved in epithelial cell fate decisions. The authors propose that Math1 expression is needed for cells to make the first lineage-specifying choice, that is, to adopt one of the following three fates: Paneth, goblet, or enteroendocrine. Without Math1, cells remain in the progenitor stem cell pool and can only become enterocytes.

To fully understand epithelial cell lineage determination in the gut, more questions need to be answered. For example, Math1 is not expressed in the stomach or pancreas, locations where Hes1-deficient mice show considerable enteroendocrine cell loss (7). This implies that there might be other factors similar to Math1 at these sites. The hedgehog family of morphogens are candidate Math1-like factors. The hedgehog signaling pathway is critical in gastric (8), pancreatic (9), and intestinal (10) epithelial cell differentiation. Although interactions between the Notch and hedgehog pathways have been described in other systems (11, 12), there is much to be learned about how these pathways interact in gut epithelium.

Yang et al.'s findings do not solve the puzzle of how epithelial cell differentiation is influenced by the cell's position along the crypt-to-villus axis. Cell fate decisions modulated by the crypt-to-villus axis are likely to involve morphogens expressed in the mesoderm and endoderm. A morphogen gradient of Bmp4, for example, may extrinsically regulate the outcome of Notch signaling in progenitor stem cells. Bmp4, a secreted morphogen expressed by the mesoderm (13), may be important in development of the intestinal epithelium (14) and is known to affect Math1-regulated cell fate decisions in other systems (15, 16). Elucidating different molecular regulators of epithelial cell differentiation along the crypt-to-villus axis will be the focus of future work.

With the Yang et al. results, we can now begin to understand the signals needed for intestinal epithelial cell fate decisions. It is interesting that one molecule, Math1, provides the signal for cells to pick one of three fate choices, leaving the enterocyte as the default state. Whether a different signal would be required for gut epithelial precursor cells to become enterocytes in Math1-deficient animals has yet to be investigated. Doubtless, many interesting discoveries about intestinal cell fate decisions will be revealed in the near future.

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