熊本大学発生医学研究所／ P21-22 【英訳】Division of Organogenesis

Kidney Development

The kidney: among the most complex of all organs
Carving out a new path toward treating kidney failure
By clarifying developmental mechanisms
and examining the possibilities of regeneration
Among all the internal organs, the kidney is acknowledged as being particularly complex.
At present, decline in kidney function cannot be repaired.
Professor Ryuichi Nishinakamura is working on establishing the mechanisms of kidney development,with the hope that his research will one day help make kidney regeneration possible,
thereby opening the way for new treatments of kidney failure.

Professor

Ryuichi Nishinakamura

Aiming for kidney regeneration
using Sall1 as an indicator

Discovering the gene vital tokidney growth

Do not be afraid of failure,and face up the challenge

The kidney is a very complex organ, which is perhaps
why there are so few researchers working on its
developmental mechanisms with the intention offeeding research output into developing regenerative
therapies. “To be honest, when I first started myresearch in kidney development, I was not really surewhat to do. I was fumbling around, without clear
direction,” says Dr. Nishinakamura, recalling his early
research. “I spent about three years working with frog
models, t r y i ng to ident i f y genes t hat a ffec t
development. Finally, I was able to identify the Sall1
gene, through a series of experiments using knockout
mouse models”. This gene, which had been so hard tofind, plays a vital role in kidney development, to theextent that deficiency in Sall1 will cause kidneyagenesis.

Dr. Nishinakamura proved the importance of Sall1
beyond doubt, but the genes functioning up anddownstream of Sall1 remain undiscovered, as do thegenes that are the target of the regulatory activity ofSall1. Recently, the team at Dr. Nishinakamura’slaboratory has discovered that a gene named Kif26b isdirectly targeted by Sall1. The absence of Kif26b results,
similarly, in kidney agenesis. “This is the result of sevenyears of research. It is another step towards realizing
kidney regeneration.”

The kidney has a vital role to play in the functioning ofthe body: it removes waste material from the body as
urine and regulates the volume of water within thebody. Severe decline in kidney function will have a fatal
effect on maintaining life. At present, the main
treatment in place for kidney failure is artificial dialysis.
But this option does nothing to recover the function of
the damaged kidneys.

The team has also discovered a gene named Dullard.
“In a Dullard-knockout mouse study, we were able toshow that while the embryonic mice are healthy, as
soon as they are born cell death starts to occur in thekidney causing a cavity in the organ, and lethality
within eight weeks after birth. The conclusion we candraw from this is that while Sall1 is vital for kidneyformation, Dullard has an important role to play inmaintaining the kidney,” says Dr. Nishinakamura. The
results of these findings were published in the Nature
Communications on January 29, 2013. “Dullard works
to regulate the signaling of BMP, a factor that causes
cell death. We further established that the condition of
Dullard-knockout mice could be improved throughthe injection of drugs designed to constrain BMP
signaling.” If the mechanisms behind the maintenanceand growth of the kidney can be uncovered, thisknowledge will shed light on the processes that cause
kidney failure in young children, as well as otherkidney-related conditions.

Continuing with his research, Dr. Nishinakamura wasable to determine that the kidney develops from several
different types of cell clusters, and that kidneydevelopment shares aspects similar to stem cell biology.
To date, it has been established that progenitor cells, thebuilding blocks of the kidney, express Sall1 verystrongly. Genes other than Sall1 have also been
identified, and have subsequently been demonstrated
as important to kidney development. “By examining
the mechanisms of kidney development, one by one,and using Sall1 as an indicator, I hope that we will beable to induce kidney progenitor cells from embryonicstem and induced pluripotent stem cells and use thoseto further our research into kidney regeneration,” says
Dr. Nishinakamura.

ryuichi@kumamoto-u.ac.jp

ProfileGraduated from the Faculty of Medicine, The University of Tokyo. He thenworked as a physician of internal medicine for four years, at The Universityof Tokyo Hospital and Jichi Medical University Hospital, among others.
In 1991, he began research at The Institute of Medical Science at The
University of Tokyo.
In 1993, he became a research fellow at DNAX Research Institute in theUnited States.
In 1996, he completed a doctoral degree at the Graduate School ofMedicine, The University of Tokyo.
He then took up a position as a research assistant at The Institute ofMedical Science at The University of Tokyo, and then a visiting associate
professor at the same institute.
In 2004, he joined the Institute of Molecular Embryology and Genetics
Center at Kumamoto University as a professor, and in 2010 the Deputy
Director of the Institute.

References●Fujimoto, Y., Tanaka, S.S., Yamaguchi, Y.L., Kobayashi, H., Kuroki,S., Tachibana, M., Shinomura, M., Kanai, Y., Morohashi, K.,
Kawakami, K., and Nishinakamura, R. Homeoprotein Six1 and Six4
regulate male sex determination and mouse gonadal development.
Dev. Cell 26: 416-430, 2013.
●Sakaguchi, M., Sharmin, S., Taguchi, A., Ohmori, T., Fujimura, S.,
Abe, T., Kiyonari, H., Komatsu, Y., Mishina, Y., Asashima, M., Araki,E., and Nishinakamura, R. The phosphatase Dullard negativelyregulates BMP signalling and is essential for nephron maintenanceafter birth. Nat. Commun. 4: 1398, 2013.
●Uchiyama, Y., Sakaguchi, M., Terabayashi, T., Inenaga, T., Inoue, S.,
Kobayashi, C., Oshima, N., Kiyonari, H., Nakagata, N., Sato, Y.,
Sekiguchi, K., Miki, H., Araki, E., Fujimura, S., Tanaka, S.S., andNishinakamura, R. Kif26b, a kinesin family gene, regulates adhesionof the embryonic kidney mesenchyme. Proc. Natl. Acad. Sci. USA
107: 9240-9245, 2010.
●Fujimura, S., Jiang, Q., Kobayashi, C., and Nishinakamura, R. Notch2
activation in the embryonic kidney depletes nephron progenitors. J.
Am. Soc. Nephrol. 21: 803-810, 2010.

21Severe cavity formationin Dullard knockout (KO) mouse kidney
control

Dullard KOA“My young researchers are not afraid of testing theirideas, and indeed they have produced some great
results. Nature is so much greater than humanknowledge and understanding. That is what makes it sofascinating. If we are to have any hope to uncovernature’s secrets with science, we need to push forward,
without being afraid of failure. I urge you to keep
asking yourself whether you are living up to theexpectations of the patients whose lives could be
improved by your research. I would like you to keep
your motivation levels high and remain ver ycommitted to your research.”

Renal aplasia in
Sall1 KO mice
KidneyEstablishment of a method for
culturing renal precursor cells

KidneyEarly stages ofrenal development
Bladder

NormalBladder

Sall1-deficient

Developmental
research
Identification of new genes
using Sall1-GFP mice

B

Looking at the potential for organ regeneration, thekidney is thought to present a particular challenge.
Even if we succeed in explaining and understandingt he mechanisms of k idney development andmaintenance, it will doubtless be a long time before any
such findings may be translated into clinicalapplications. “It is exactly the challenging nature of thisresearch, and this organ, that has meant few
laboratories have studied kidney development to theextent that we do. This allows me and my team toundertake highly original research,” says Dr.
Nishinakamura, clearly passionate about his subject.

Dullard
BMP

Apoptosis

Single cell

Renal mesenchyme

Ureteric bud

Colony formation

Regenerative
research
Induction of renal cells
from ES cells

Dullard
BMP

Apoptosis

Renal agenesis in Kif26b KO mice

Teaching Staff
Assistant Professor

Satomi S. Tanaka
My research focuses on the formation and differentiation ofmouse germline cells, speciﬁcally how next-generation
germline cells are produced, and how they are different
from stem cells and somatic cells. My desire to answer
these questions is what drives my research. I am also
studying the structure of male and female sex differences,which form the basis of sexual reproduction.

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