Japanese molecular biologist
Masashi Yanagisawa (柳沢 正史 , Yanagisawa Masashi , born May 25, 1960) is a Japanese-American
molecular biologist and physician, famous for his discovery of the
hormone
endothelin and the
neuropeptide
orexin , the absence of which is the cause of
narcolepsy . He is currently the Director of the International Institute for Integrative Sleep Medicine,
University of Tsukuba , and an adjunct professor at the Department of
Molecular Genetics ,
University of Texas Southwestern Medical Center .
[3]
Early life and education
Yanagisawa was born in Tokyo in 1960. His father was a surgeon and, thanks to his background in
electrical and
electronic engineering , an
electrophysiology researcher.
[4] He graduated from
Musashi Junior and Senior High School in 1979, and entered the
University of Tsukuba to study medicine. After obtaining an
MD in 1985, he pursued a PhD at the same institute, completing it 3 years later.
[3]
Career
Immediately after obtaining his PhD, Yanagisawa started his career as a
postdoctoral fellow at the Department of
Pharmacology of the
University of Tsukuba .
[3] One year later, he became an assistant professor at the same department, and in 1991 moved to the
Kyoto University
School of Medicine as an assistant professor at the Department of Pharmacology.
[5]
Yanagisawa stayed at
Kyoto only for one year, after which
Joseph L. Goldstein and
Michael Stuart Brown , both 1985
Nobel Prize in Physiology or Medicine laureates and famous for their research in
cholesterol , recruited him to the
University of Texas Southwestern Medical Center (UTSW).
[1] He began as an
associate professor at the Department of
Molecular genetics ,
[6] was promoted to
full professor in 1996,
[5] and endowed with the
Patrick E. Haggerty Distinguished Chair in Basic Biomedical Science in 1998.
[2]
Between 2001 and 2006, he had his own project under the
Japan Science and Technology Agency ERATO (Exploratory Research for Advanced Technology) scheme, focusing on discovering
endogenous
ligands for
orphan receptors .
[7]
He returned to Japan in 2012 to found and direct the International Institute for Integrative Sleep Medicine at the University of Tsukuba, which was established under the World Premier International Research Center Initiative by Japan's
Ministry of Education, Culture, Sports, Science and Technology .
[8] Two years later, he switched to part-time at UTSW as an
adjunct professor .
[5] Yanagisawa was also an investigator at the
Howard Hughes Medical Institute during his time working full-time at UTSW.
[9]
Research
Yanagisawa is most well known for his discovery of the
hormone
endothelin and the
neuropeptide
orexin . Early 1980s saw the revelation that
nitric oxide was the substance
endothelial cells produce to relax the
smooth muscle around
blood vessels , which causes
vasodilation and increased blood flow.
[10] This led to the speculation of and hunt for the inverse, an endothelium-derived
vasoconstricting substance.
[11] During his PhD study, Yanagisawa's supervisor, Tomoh Masaki, agreed to let him try to isolate the substance. This study became his PhD thesis, and he published his finding it 1988, naming the substance "endothelin" and reporting its peptide sequence.
[12] He then published a number of reports on the function and regulation of endothelin, including working with Takeshi Sakurai to identify the
receptor
for endothelin .
[13]
He kept studying endothelin after moving to the
University of Texas Southwestern Medical Center (UTSW) in the United States, for example discovering one of the mechanisms to activate endothelin
[14] and that a mutation in endothelin receptor can cause
Hirschsprung's disease .
[15]
Eventually, his interest in endothelin diminished and Yanagisawa switched his focus to
orphan receptors , which are receptors whose
endogenous
ligands have yet to be identified, particularly orphan
G protein-coupled receptors (GPCRs). In 1998, again teaming up with Takeshi Sakurai, who has moved to the United States as a
postdoctoral fellow at UTSW, Yanagisawa connected two orphan GPCRs with a family of
neuropeptides as their ligands. They named it "
orexin " after the
Greek word for appetite, since the neuropeptide was found exclusively in the
hypothalamus , a brain region that regulates appetite, and because
mice consumed more food after receiving a dose of orexin.
[16] Another group at
The Scripps Research Institute (now
Scripps Research ) made the same discovery in the same year, and named the neuropeptide "hypocretin".
[17] Today, "hypocretin" (or HCRT ) is used to refer to the
gene and
transcript , while "orexin" is used to refer to the
peptide .
[18]
Yanagisawa and his team then
knocked out the orexin
gene in mice, hoping to see the animal eating less. Instead, they observed behavior similar to the human condition of
narcolepsy , whose cause at the time was still unknown.
[19] The association between orexin and narcolepsy was definitively established not long afterwards in 2000.
[20]
Since then, his research has mostly focused on studying
sleep and orphan receptors. For example, he uncovered the functions of
GPR7 (NPBW1) and
GPR8 (NPBW2),
[21]
GPR41 (FFA3),
[22] and
GPR103 (QRFPR).
[23]
More recently, using an unbiased
forward genetics approach, which randomly introduced
mutations in mice and then observed their
electrocardiogram and
electromyogram , Yanagisawa and his team reported the role of
KIAA0999 (encoded by the Sik3 gene) and NALCN (encoded by the Nalcn gene) in regulating sleep.
[24]
[25] His team also identified the
phosphorylation and
dephosphorylation of 80 proteins as a major regulation mechanism of the
sleep cycle in mice.
[26]
Honors and awards
Personal life
Yanagisawa is married, and is a
Baptist
Christian since his second year of PhD.
[42] He plays the flute.
[6]
References
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"ECE-1: A membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1" .
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"A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease" . Cell . 79 (7): 1257–1266.
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"Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior" . Cell . 92 (4): 573–585.
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"The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity" .
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"Narcolepsy in orexin Knockout Mice: Molecular Genetics of Sleep Regulation" . Cell . 98 (4): 437–451.
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^ Peyron, Christelle; Faraco, Juliette; Rogers, William; Ripley, Beth; Overeem, Sebastiaan; Charnay, Yves; Nevsimalova, Sona; Aldrich, Michael; Reynolds, David; Albin, Roger; Li, Robin; Hungs, Marcel; Pedrazzoli, Mario; Padigaru, Muralidhara; Kucherlapati, Melanie; Fan, Jun; Maki, Richard; Lammers, Gert Jan; Bouras, Constantin; Kucherlapati, Raju; Nishino, Seiji; Mignot, Emmanuel (2000).
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"Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8" . Proceedings of the National Academy of Sciences . 100 (10): 6251–6256.
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^ Xiong, Yumei; Miyamoto, Norimasa; Shibata, Kenji; Valasek, Mark A.; Motoike, Toshiyuki; Kedzierski, Rafal M.; Yanagisawa, Masashi (2004).
"Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41" . Proceedings of the National Academy of Sciences . 101 (4): 1045–1050.
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"A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice" . Proceedings of the National Academy of Sciences . 103 (19): 7438–7443.
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^ Funato, Hiromasa; Miyoshi, Chika; Fujiyama, Tomoyuki; Kanda, Takeshi; Sato, Makito; Wang, Zhiqiang; Ma, Jing; Nakane, Shin; Tomita, Jun; Ikkyu, Aya; Kakizaki, Miyo; Hotta-Hirashima, Noriko; Kanno, Satomi; Komiya, Haruna; Asano, Fuyuki; Honda, Takato; Kim, Staci J.; Harano, Kanako; Muramoto, Hiroki; Yonezawa, Toshiya; Mizuno, Seiya; Miyazaki, Shinichi; Connor, Linzi; Kumar, Vivek; Miura, Ikuo; Suzuki, Tomohiro; Watanabe, Atsushi; Abe, Manabu; Sugiyama, Fumihiro; Takahashi, Satoru; Sakimura, Kenji; Hayashi, Yu; Liu, Qinghua; Kume, Kazuhiko; Wakana, Shigeharu; Takahashi, Joseph S.; Yanagisawa, Masashi (2016).
"Forward-genetics analysis of sleep in randomly mutagenized mice" . Nature . 539 (7629): 378–383.
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