Mammals share gene pathways that allow zebrafish to grow new eyes
Study may advance genetic therapies for blindness and other injuries to
the central nervous system

Date:
October 7, 2020
Source:
Johns Hopkins Medicine
Summary:
Working with fish, birds and mice, researchers report new evidence
that some animals' natural capacity to regrow neurons is not
missing, but is instead inactivated in mammals.



FULL STORY ========================================================================== Working with fish, birds and mice, Johns Hopkins Medicine researchers
report new evidence that some animals' natural capacity to regrow neurons
is not missing, but is instead inactivated in mammals. Specifically,
the researchers found that some genetic pathways that allow many fish
and other cold-blooded animals to repair specialized eye neurons after
injury remain present in mammals as well, but are turned off, blocking regeneration and healing.


==========================================================================
A description of the study, published online by the journal Science
on Oct. 1, offers a better understanding of how genes that control
regeneration are conserved across species, as well as how they
function. This may help scientists develop ways to grow cells that are
lost due to hereditary blindness and other neurodegenerative diseases.

"Our research overall indicates that the potential for regeneration is
there in mammals, including humans, but some evolutionary pressure has
turned it off," says Seth Blackshaw, Ph.D., professor of neuroscience at
the Johns Hopkins University School of Medicine. "In fact, regeneration
seems to be the default status, and the loss of that ability happened
at multiple points on the evolutionary tree," he says.

For the study, Blackshaw's team focused on supportive cells in the back
of the eye. In zebrafish, a standard laboratory model whose genome has
been well defined, these cells, known as Mu"ller glia, respond and repair
the light- sensitive retina by growing new cells in the central nervous
system called neurons. In addition to regrowing eye tissue, zebrafish's regenerative abilities extend to other body parts, including fins,
tails and some internal organs.

The retina is a good testing ground for mapping genetic activity, explains Blackshaw, because it contains structures common to other cells in the
nervous system. In previous studies, moreover, scientists have found that
the genetic networks in the retina are well conserved across species,
so comparisons among fish, birds, mice and even humans are possible.

For the new experiments, the Johns Hopkins researchers created retinal
injuries in zebrafish, chickens and mice. Then they used high-powered microscopes and a previously developed gene mapping tool to observe how
the supportive Mu"ller glia cells responded.



========================================================================== Blackshaw said the team was surprised to find, immediately after the
injury, that the cells in each of the three species behaved the same
way: They entered an "active state" characterized by the activation of
specific genes, some of which control inflammation.

This active state, says Blackshaw, primarily helps to contain the injury
and send signals to immune system cells to combat foreign invaders such
as bacteria, or to clean up broken tissue.

Beyond that step, however, the species' responses diverged.

In zebrafish, active Mu"ller glia began turning on a network of
transcription factors that control which genes are 'on' and 'off.' In
the current experiment, the NFI transcription factors activated genes
that are linked to cell maturity, sending the Mu"ller glia cells back
in developmental time to a more primitive state, which then allows
them to develop into many different cell types. The Mu"ller glia then "differentiated" into new cells to replace the ones lost to injury.

In contrast, the research team saw that chickens with damaged retinas
activate only some of the transcription factor 'gene control switches'
that are turned on in zebrafish. Thus, chickens have much less capability
to create new Mu"ller glia and other neurons in the eye following injury.



========================================================================== Finally, the researchers looked at the injury response in mice. Mice
share the vast majority of their DNA with humans, and their eyes are
similar to human eyes. The researchers found that injured Mu"ller glia
in mice remained in the first "active" state for several days, much
longer than the eight to 12 hours that zebrafish are in this state,
and yet never acquired the ability to make new neurons.

Mu"ller glia in all three species also express high levels of nuclear
factor I (NFI) transcription factors, but rapidly turn them off
following injury. In mice, however, the NFI genes are turned back on soon thereafter, and actively block the Mu"ller glia from generating neurons.

The researchers found, to their surprise, they say, that the same genes
that allowed the zebrafish cells to regenerate were "primed and ready
to go" in the mouse eye, but that the "on" transcription factor was
never activated. Instead, the NFI factors actively block the cells' regenerative potential.

Blackshaw suspects that animals with a higher potential to develop disease
in brain and other neurological tissue may have lost this capability over evolutionary time to help protect and stabilize other brain cells. "For example, we know that certain viruses, bacteria and even parasites can
infect the brain. It could be disastrous if infected brain cells were
allowed to grow and spread the infection through the nervous system,"
says Blackshaw.

Now equipped with a more detailed map of the cellular response to neuronal injury and regrowth, scientists may be able to find a way to activate
the regenerative capabilities hidden in human DNA, Blackshaw says.

Video: https://www.youtube.com/watch?v=9mooOuYbd6c&feature=emb_logo

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


========================================================================== Journal Reference:
1. Thanh Hoang, Jie Wang, Patrick Boyd, Fang Wang, Clayton Santiago,
Lizhi
Jiang, Sooyeon Yoo, Manuela Lahne, Levi J. Todd, Meng Jia, Cristian
Saez, Casey Keuthan, Isabella Palazzo, Natalie Squires, Warren
A. Campbell, Fatemeh Rajaii, Trisha Parayil, Vickie Trinh, Dong Won
Kim, Guohua Wang, Leah J. Campbell, John Ash, Andy J. Fischer,
David R. Hyde, Jiang Qian, Seth Blackshaw. Gene regulatory
networks controlling vertebrate retinal regeneration. Science,
2020; eabb8598 DOI: 10.1126/science.abb8598 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201007123110.htm

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