熊本大学発生医学研究所／ P17-18 【英訳】
Division of Stem Cell Research
Cell Fate Control
“Conversations” control proliferation of cells
This intercellular communication
provides vital clues for unraveling
the core principles of development
Communication between cells plays a vital role in ensuring the body develops normally.
By coming into contact and conversing with each other, cells are able to understand
which type of tissue or organ they need to become part of,
and are also able to control proliferation and viability.
Trying to discover more about the mechanisms of the conversations held
between cells is one of the core topics of Dr. Sasaki’s research.
Professor
Hiroshi Sasaki
The signal center: gives
commands to cells
How can it be that the human body is able to develop from
a single fertilized egg? “There is so much potential for
mistakes to happen in the developmental processes,” says
Dr. Sasaki, “so examining how the body manages to
develop itself, while self-regulating any abnormalities, is an
incredibly interesting topic.”
The fertilized egg of mammals, such as humans and mice,
go through initial development in a very different style to
oviparous vertebrates such as frogs and chickens. The
fertilized egg of a frog, for example, contains the localized
information (dorsal determinants) needed to form a body.
In contrast, a fertilized mouse egg does not have that
information. “The mouse egg does not contain the
information it needs to develop into a body. So in order for
the egg to differentiate and the necessary tissue and organs
to be generated, there needs to be good communication
between cells known as signal centers and the
surrounding cells.”
If these signal centers are not able to give commands
to other cells, instructing them about what to
become, then the surrounding cells do not know
how to differentiate. This means that the body
cannot develop. The clarification of the mechanism
of the long-range intercellular communication used
to send out the necessary signals is one of the core
areas of Dr. Sasaki’s research.
Another key pillar of his research is short-range
communication between neighboring cells. One
outcome of contact-based communication between
cells is cell competition, which results in the
elimination of weaker cells. The winner cells then
compensate for the elimination of weaker cells, thereby
creating a system in which cells mutually control their
respective proliferation and viability.
these Hippo signaling pathways are present in
humans and mice.
“In cultured cells, it is known that cells proliferate when
there is a low level of direct cell-to-cell contact, and that
proliferation stops when direct cell-to-cell contact is
frequent. What we did not know was how. Through
experiments with mouse cell culture, we found that when
there was low contact between cells, Hippo signaling
became weaker, and the coactivator protein Yap would
accumulate to nuclei, activating a transcription factor and
causing the cell to proliferate. When the Hippo signaling
became stronger, however, Yap was excluded from nuclei,
suppressing the activity of the transcription factor, and
preventing proliferation.”
“Take the example of a patient with advanced liver failure.
In some cases, a living-donor liver transplantation, in
which part of the liver of a family member or other suitable
donor is transplanted into the patient, could be performed.
Part of the liver of the donor must be excised in this
process, but after a while the donor’s liver will return to its
original size. This is due to the communication between
the cells, which serves to control the regeneration of the
liver, signaling the extent to which the liver has to grow in
order to return to its normal state. Epidermal cells, in the
skin, small intestine, and bone, for example, need to
replace themselves at regular intervals; it is vital that the
right cells are replaced in the right amounts at the right
time. We know that intercellular communication has a
very important role in this process,” explains Dr. Sasaki.
His team succeeded in discovering the crucial part played
by Hippo signaling pathways in communication
mediated through direct cell-to-cell contact.
If we culture pre-implantation mouse embryos, we
can see differentiation into two kinds of cells: those
that will form the placenta and those that will form
the body of the mouse. What this means is that the
position of the cells determines what they will
become, and t his is caused by t he locationa l
differences in the level of Hippo signaling activity.
“We will continue to elucidate how Hippo signaling
is able to alter its level of activity,” says Dr. Sasaki.
Dr. Sasaki’s commitment to the new research field of
intercellular communication looks set to remain
unwavering. “By shedding light on the role of intercellular
communication in embryogenesis and by looking at how
abnormalities in intercellular communication may cause
disease, including cancer, we hope to make tangible
contributions to progress in regenerative medicine and the
development of new treatments of disease.”
Hippo signaling to control
communication
Hippo signaling was originally identified as a tumor
suppressor–signaling pathway in Drosophila. It has
also been established, however, that genes related to
Cells communicate
through direct contact
[email protected]
Profile
Born in Toyama prefecture in 1962.
Graduated with a Bachelor’
s degree from the Department of Biological Science,
School of Science, The University of Tokyo, then went on to obtain a doctorate
(with specialization in zoology) from the Graduate School of Science of the same
university. Holds a Ph.D.
In 1990, he began work as a research associate at the Research Institute for Chest
Diseases and Cancer, Tohoku University.
In 1992, he took up a role as a research associate at the Vanderbilt University
School of Medicine.
In 1995, he became a assistant professor at the Institute for Molecular and Cellular
Biology at Osaka University.
In 2002, he joined the RIKEN Center for Developmental Biology as a team leader.
In 2010, he began working as a professor as the Institute of Molecular Embryology
and Genetics at Kumamoto University.
References
●Hirate Y, Cockburn K, Rossant J, *Sasaki H (2012)
Tead4 is constitutively nuclear, while nuclear vs. cytoplasmic Yap distribution is
regulated in preimplantation embryos.
Proc. Natl. Acad. Sci. USA. 109:E3389-90. doi: 10.1073/pnas.1211810109
●Wada K-I, Itoga K, Okano T, Yonemura S, *Sasaki H (2011)
Hippo pathway regulation by cell morphology and stress fibers.
Development 138, 3907-3914.
●Nishioka N, Inoue K-I, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N,
Hirahara S, Stephenson RO, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki
EM, Nojima H, Rossant J, Nakao K, Niwa H, *Sasaki H. (2009)
The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to
distinguish mouse trophectoderm from inner cell mass.
Dev. Cell 16, 398-410.
●Ota M, *Sasaki H. (2008)
Mammalian Tead proteins regulate cell proliferation and contact inhibition as a
transcriptional mediator of Hippo signaling.
Development. 135, 4059-4069
●Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y, Yonemura S, Tarui H,
*Sasaki H (2008)
Cthrc1 selectively activates planar cell polarity pathway of Wnt signaling by
stabilizing Wnt-receptor complex.
Dev. Cell 15, 23-36.
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Long distance communication
“Make a head!”
Neighboring communication
“We collaborate together.”
“Copy that.”
OK!
“Let’s discuss and share work.”
“I will become red.”
“Got it!”
“OK, I will be blue.”
Leader
・
・
・
・
・
？
？
Without
communications....
In the absence of
communications....
？
“I want to multiply more.”
“I do not know what to become. . . .”
Ear
Loss of intercellular
communications may
lead to malformation
Normal
neonatal
mouse
The body will lack necessary cells
A normal mouse embryo incubated
5 days on a culture plate
Neonatal mutant mouse
lacking cells directing
differentiation into the head.
Mouse
transplanted
with normal
organ cells
Teaching Staff
“So do I.”
“No one is willing to become blue... ”
Cancer will develop.
Ear
“I want to become red.”
Mouse
transplanted
with cells
lacking cellular
communication
capabilities
Organ hyperplasia may develop.
Assistant Professor
Body-forming cells Placenta-forming cells
An abnormal mouse
embryo containing cells lacking
cellular communication capabilities after
5-day incubation on a culture plate
Yoshikazu Hirate
My research focuses on cell differentiation in preimplantation
mouse embryos. When my data produces truly significant findings,
I get a real sense of satisfaction as a researcher. I would encourage
all students to be bold in taking on tough research issues and to
build up experience in overcoming such challenges. When you
find yourself facing difficulty out in the real world, it is just this sort of
experience that will come to your aid.
Normal
mouse liver
Abnormal mouse
liver containing
hepatocytes
lacking cellular
communication
capabilities
Body-forming cells
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