Scientists create novel genetic model of Down syndrome in rats

Date:
March 14, 2022
Source:
Johns Hopkins Medicine
Summary:
In pursuit of better ways to test new therapies and further explore
the impacts of the unique genetics associated with Down syndrome,
researchers have genetically engineered and characterized what is
believed to be the first rat model of Down syndrome.



FULL STORY ==========================================================================
In pursuit of better ways to test new therapies and further explore
the impacts of the unique genetics associated with Down syndrome,
researchers at Johns Hopkins Medicine and Tottori University in Japan
have genetically engineered and characterized what is believed to be
the first rat model of Down syndrome.


==========================================================================
A report of their research appeared Jan. 24 in The American Journal of
Human Genetics.

Scientists have long sought ways to improve medical care for people
with Down syndrome, especially those suffering the physical and mental challenges that are hallmarks of the condition. These include a higher
risk of heart defects, gastrointestinal problems and difficulties with
learning and memory.

"Developing an animal model that shares these features with human Down
Syndrome will allow us to test therapeutics more efficiently, with higher
odds of developing ones that can work in people," says Roger H. Reeves,
Ph.D., professor of physiology at the Johns Hopkins University School
of Medicine.

At its root, Down syndrome is an outcome of a so-called chromosomal
"trisomy," or tripling. A typical human cell has 23 pairs of chromosomes,
which contain genetic instructions that govern its inner workings and how
it interacts with the rest of the body. Down syndrome occurs when a person
is born with an extra partial or entire copy of the 21st chromosome,
a condition called trisomy 21.

This extra chromosome's effects are expressed widely across the body
and its impacts vary among individuals.

Rats do not -- as humans do -- randomly produce offspring with extra
21st chromosomes, so the researchers set out to accomplish a complicated
feat of genetic engineering to generate rats with an additional 21st chromosome.



==========================================================================
The process included transferring the 21st chromosome from human white
blood cells to mouse cells, then to chicken cells, then hamster cells and, finally, into a rat embryo.

At each transfer, the researchers made different genetic modifications, including the addition of a green glowing protein, which under ultraviolet light identified rats with extra 21st chromosomes.

Reeves and his team then assessed the genetically engineered rats'
cognition and physical characteristics for traits associated with an
extra 21st chromosome.

To test the rats' learning and memory, for example, the researchers
conducted standardized maze tests with the genetically engineered rats.

Rats with an extra 21st chromosome took longer to solve the maze than genetically typical rats. They also had a harder time remembering the
maze's solution when challenged to solve the same puzzle over four
consecutive days.



========================================================================== Other cognitive tests reflected that, overall, the rats with an extra
21st chromosome were more anxious and hyperactive than rats without
the extra chromosome. These results are consistent with assessments in
people with Down syndrome, who report having higher rates of anxiety,
attention disorders and learning and memory impairments.

In anatomical studies, the researchers also found that a brain structure
called the cerebellum was significantly smaller in rats with an extra
21st chromosome.

The cerebellum is central to the body's core functions, including
message processing across the brain, and is much smaller in people with
Down syndrome.

"There is already progress in developing pharmaceuticals that help the cerebellum grow in mice," says Reeves. "If we eventually translate
that into medicines for humans, we may be able to help people with
Down syndrome improve their learning and memory skills." The distinct
facial differences in people with Down syndrome -- such as flatter faces, almond-shaped eyes and smaller heads -- were also present in the rats.

While people cannot look at a rat and determine whether its face
looks different from a typical rodent, a computer program can measure
the differences. The skulls were scanned in a CT machine and the data
added to a computer modeling program, which revealed that the rats had shortened snouts.

The bones making up these features in the rat skull correspond to those
in human skulls that make up the characteristic facial "flattening"
in people with Down syndrome.

Finally, 17% of the rats with an extra 21st chromosome had an abnormality
of heart ventricles that is similar to one diagnosed in up to 21% of
children with Down syndrome.

The model will be distributed to researchers through the NIH-supported
Rat Resource and Research Center at the University of Missouri and the
National BioResource Project for the Rat in Japan. Other researchers
involved in this study include Yasuhiro Kazuki, Miho Yamakawa, Kanako
Kazuki, Naoyo Kajitani, Moeka Koshima, Masaharu Hiratsuka, Hiroshi
Kuniishi, Satoshi Ichisaka, Yoshio Hata, Yuji Nakayama and Yuich Iida
of Tottori University, Yonago, Japan; Masumi Hirabayashi, Hiromasa Hara
and Makoto Sanbo of the National Institute for Physiological Sciences,
Okazaki, Japan; Haruka Takayama, Satoshi Abe, and Shoko Takehara of Trans Chromosomics, Inc., Tottori, Japan; Feng Gao, Yicong Li, Bei Cheng and
Anna Moyer of Johns Hopkins; Satoko Matsukura and Naohiro Noda of the
National Institute of Advanced Industrial Science and Technology, Japan; Sachiko Miyagawa-Tomita of the Yamazaki University of Animal Health
Technology, Tokyo, Japan, and the University of Tokyo, Tokyo, Japan;
Nandini Singh of the California State University; Joan Richtsmeier of
Penn State University; and Mitsuo Oshimura of Tottori University, Yonago, Japan, and Trans Chromosomics, Inc., Tottori, Japan.

The work was supported by Japan Science and Technology Agency CREST, the National Institute for Physiological Sciences in Japan, the Mitsubishi Foundation and the National Institutes of Health's Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD038384, R21HD098540).


========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yasuhiro Kazuki, Feng J. Gao, Miho Yamakawa, Masumi Hirabayashi,
Kanako
Kazuki, Naoyo Kajitani, Sachiko Miyagawa-Tomita, Satoshi Abe,
Makoto Sanbo, Hiromasa Hara, Hiroshi Kuniishi, Satoshi Ichisaka,
Yoshio Hata, Moeka Koshima, Haruka Takayama, Shoko Takehara, Yuji
Nakayama, Masaharu Hiratsuka, Yuichi Iida, Satoko Matsukura,
Naohiro Noda, Yicong Li, Anna J. Moyer, Bei Cheng, Nandini
Singh, Joan T. Richtsmeier, Mitsuo Oshimura, Roger H. Reeves. A
transchromosomic rat model with human chromosome 21 shows robust
Down syndrome features. The American Journal of Human Genetics,
2022; 109 (2): 328 DOI: 10.1016/j.ajhg.2021.12.015 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220314105609.htm

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