December 07, 2001
Gene Triggers Stem Cell Differentiation
A gene that governs development of neuronal cells has now been shown
to be involved in regulating differentiation of stem cells into
secretory cells in the intestine.
The research team, which included Howard Hughes Medical Institute
investigator Huda
Zoghbi, Qi Yang, Nessan Bermingham and Milton Finegold at Baylor
College of Medicine, showed that the Math1 gene — which codes
for a gene-activating protein called a transcription factor — is
necessary for the differentiation of three kinds of intestinal cells
from stem cells. The team published its findings in the December 7,
2001, issue of the journal Science.
“What we can learn about the molecular events that trigger intestinal stem cells to differentiate could likely prove applicable to many other stem cells in other parts of the organism.”
Huda Y. Zoghbi
Previous work by Zoghbi and her colleagues revealed Math1's
role in governing differentiation of neuronal cells, including sensory
cells in the inner ear. "In the course of those earlier studies, we
detected Math1 expression in the intestine," said Zoghbi. "Its
function there was unknown. However, we knew that the gut has a nervous
system of its own, so we thought Math1 might be important for
components of that system," she said.
To pinpoint the gene's activity, the researchers genetically
engineered mice in which the coding region of the Math1 gene was
replaced by an enzyme that would stain the cells expressing the gene in
developing mouse embryos. They first examined mice with one copy of the
functional Math1 gene, along with the stain-producing gene, to
determine which cells expressed Math1.
"To our total surprise, we could not detect expression of the gene
in the nervous system of the gut, but instead found it in the
intestinal epithelium," said Zoghbi. These studies revealed that three
kinds of secretory cells expressed Math1. These were goblet
cells that secrete mucous important for food movement; enteroendocrine
cells that secrete regulatory peptides, and Paneth cells that secrete
microbe-fighting peptides. The researchers did not find Math1
expression in other intestinal cells, called enterocytes, which also
arise from a common stem cell lineage. In contrast to secretory cells,
enterocytes play a role in absorbing nutrients.
"When we studied the mutants with no Math1, we found that all
three secretory cell types were missing," said Zoghbi. "This told us
that Math1 was important for basic stem cell differentiation,
and that Math1 -negative progenitor cells gave rise to the
enterocytes, whereas Math1 -expressing cells give rise to
goblet, enteroendocrine and Paneth cells," she said. "Researchers knew
from previous work that one type of stem cell gives rise to all these
cell types, but now we know that Math1 likely plays a key role in the
decision whether to become a secretory or an absorptive cell."
Additional studies revealed that the protein produced by the
Math1 gene appears to regulate the Delta-Notch signaling pathway
that governs endocrine cell differentiation. According to Zoghbi, the
discovery of Math1's role constitutes a significant step toward
understanding how intestinal stem cells differentiate.
"A few months ago all we knew was that in the gut there is a stem
cell that is self-renewing and that gives rise to a variety of cell
types," she said. "We had no clue what happens to make this stem cell
into a mucous-secreting cell or a peptide-secreting cell, or an
absorptive cell. Now we have Math1 to help us begin to build a
framework of understanding of the cascade of events, involving many
genes, that governs this process."
Such an understanding could have considerable clinical importance,
said Zoghbi. "These cells are important in our handling of metabolites
absorbed from food and our response to infections," she said. "So, one
could imagine a basic understanding of them leading to new treatments
for such diseases as irritable bowel syndrome and other abnormalities
of gut motility. Also, since these intestinal cells depend on these
regulatory pathways to signal them to stop proliferating, understanding
those pathways could yield insights into the mechanisms of colon
cancers." In the longer term, said Zoghbi, understanding the regulatory
control of intestinal stem cells could lead to treatments to regenerate
damaged intestinal tissue.
"While it will take considerable work to get to that point, one
could envision providing dormant stem cells with some regulatory
factors to push them to proceed down a path of differentiation, to
replace cells lost to injury," she said. Finally, she said, discoveries
about intestinal stem cells could be generalizable to other stem
cells.
"What we can learn about the molecular events that trigger
intestinal stem cells to differentiate could likely prove applicable to
many other stem cells in other parts of the organism," Zoghbi said.
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