Research Area: Stem Cell and Developmental Biology

The proteins that package DNA to fit inside cells have another role: tuning gene expression
Raleigh McElvery
May 19, 2021

The DNA inside a single human cell is several meters long — yet it must be condensed to fit inside a space one-tenth the diameter of a hair. That’s like stretching a string from Philadelphia, Pennsylvania to Washington, D.C., and then trying to stuff it into a soccer ball. Imagine then organizing all of this information for each of the body’s 3 trillion cells! The DNA is condensed by proteins called histones that create a spool around which the DNA can wrap itself. How tightly the DNA is wound determines whether it is accessible enough for other proteins to bind to and copy into RNA, toggling gene expression levels up or down.

One specialized type of histone, H2A.Z, is ubiquitous and essential among multicellular organisms. But there have been conflicting reports about how it affects gene expression, especially during embryonic development.

Several years ago, Laurie Boyer’s lab at MIT was the first to show that H2A.Z wraps the DNA located around the start sites of most genes, where the molecular machine RNA polymerase II (RNAPII) binds to copy the DNA into RNA. Boyer’s team demonstrated that removing H2A.Z prevented embryonic cells from turning on genes that are important for forming organs and tissues. But scientists still weren’t sure how H2A.Z exerted its effects.

Now, in a recent Nature Structural and Molecular Biology study, a team from the Boyer lab, led by former postdoc Constantine Mylonas, has revealed how H2A.Z regulates the ability of RNAPII to properly transcribe DNA into the messages that specify all cell types in the body. The researchers found that in embryonic stem cells, H2A.Z serves as a “yellow traffic light,” signaling RNAPII to slow the process of transcribing DNA into RNA. Although there are other proteins that also contribute to RNAPII pausing, H2A.Z establishes a second barrier to transcription that allows gene expression to be tuned in response to developmental signals.

“H2A.Z appears to regulate how fast RNAPII begins to transcribe DNA, and this allows the cell time to respond to important cues that ultimately direct a stem cell to become a brain or heart cell, for example,” says Boyer, a professor of biology and biological engineering. “This connection was a critical missing piece of the puzzle, and explains why H2A.Z is essential for development across all multicellular organisms.”

Illustration of molecules
As RNAPII starts to transcribe a gene, it encounters a cluster of eight histones (a “nucleosome”) including H2A.z, which slows its progression — allowing for tuning of gene expression in response to developmental signals.

According to Boyer, H2A.Z’s role in gene expression has been difficult to pin down because previous approaches only provided static snapshots of how proteins interact with DNA days after loss of the histone. Boyer’s team overcame this shortcoming by leveraging a system that allowed for targeted degradation of H2A.Z within hours. They combined this technique with high-resolution genomic approaches and live cell imaging of RNAPII dynamics using super-resolution microscopy. With help from Ibrahim Cissé’s lab, they were able to visualize RNAPII dynamics in real time at the single molecule level in embryonic stem cells. Upon loss of H2A.Z, they found a remarkable increase in RNAPII movement in the cells, consistent with their genomic results showing a faster release of RNAPII and an increase in transcription in the absence of H2A.Z.

Next, the researchers plan to determine precisely how H2A.Z is targeted to the start sites of genes and how it forms a barrier to RNAPII passage.

Boyer says pinpointing the way histone variants like H2A.Z control gene expression is fundamental to understanding how developmental decisions are made, and will help researchers understand why misregulation of H2A.Z has been linked to diseases such as cancer.

“Emerging evidence indicates that DNA ‘packaging proteins’ like histones directly participate in how RNAPII can read and transcribe DNA,” she explains, “and that crucial connection wasn’t clear before.”

Image credits: courtesy of Laurie Boyer
Top image: Live cell super-resolution imaging showing RNAPII dynamics at a single molecule level in embryonic stem cells. The bright and colored clusters represent RNAPII molecules.

Citation:
“A dual role for H2A. Z. 1 in modulating the dynamics of RNA Polymerase II initiation and elongation.”
Nature Structural & Molecular Biology, online May 10, 2021, DOI: 10.1038/s41594-021-00589-3
Constantine Mylonas, Choongman Lee, Alexander L. Auld, Ibrahim I. Cisse, and Laurie A. Boyer.

Kristin Knouse

Education

  • PhD, 2017, MIT; MD, 2018, Harvard Medical School
  • Undergraduate: BS, 2010, Biology, Duke University

Research Summary

We aim to understand how tissues sense and respond to damage with the goal of developing novel treatments for diverse human diseases. We focus on the mammalian liver, which has the unique ability to completely regenerate itself, in order to identify the molecular requirements for effective organ repair. To this end, we innovate genetic, molecular, and cellular tools that allow us to investigate and modulate organ injury and regeneration directly within living organisms.

Awards

  • NIH Director’s Early Independence Award, 2018
  • Henry Asbury Christian Award, 2018
These worms’ stem cells are developmental shapeshifters
Eva Frederick | Whitehead Institute
April 20, 2021

Planarians are small water-dwelling worms known for their regenerative capacity. If you chop one into ten pieces, you’ll end up with ten fully-formed worms.

While humans have pools of specialized stem cells that can create our regenerative body parts like hair and skin, these worms owe their regenerative superpowers to a special kind of stem cell called a neoblast. At least some of these cells are “pluripotent,” meaning that they can divide to create almost any cell type in a worm’s body at any time. Neoblasts are actually the only dividing cells in planarians — fully committed cells like those in the eyes or intestines cannot divide again.

“The big question for us is, how does a neoblast go from being able to make anything, to making one particular thing?” says Amelie Raz, a postdoctoral researcher at Whitehead Institute who conducted her graduate research in the lab of Whitehead Institute Member Peter Reddien. “How do they go from being able to make anything in the body to being, say, an intestine cell that’s going to stay an intestine cell until it dies?”

Now, in a paper published online April 20 in the journal Cell Stem Cell, researchers at Whitehead Institute lay out a new model for how these stem cells commit to their fates and go on to create fully differentiated cells. The process of cellular differentiation is often viewed as a hierarchy, with one special stem cell at the top which can take a number of potential paths to arrive at a specialized state. This is generally thought to take place over a series of cell divisions in which each generation’s fate is gradually restricted.

“We’re proposing something happens that is very different from the conventional view,” says senior author Reddien, who is also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute. “We think that stem cells can make broad jumps in state without going through a series of fate-restricting divisions. We call it the single-step fate model.”

In the new model, neoblasts that are on a path toward creating skin cells or intestine cells can produce progeny cells that can switch fates to create cells of other types. The work is a step in the long road to understanding these worms’ regenerative capacities, and could possibly inform regenerative medicine approaches far in the future.

“The ability of planarian stem cells to essentially switch their fate is really, really powerful,” says Raz, the first author of the paper. “Obviously this is a long way off, but theoretically the concept of stem cell fate switching could be applied to regenerative medicine, with human stem cell programming.”

Upturning the hierarchy

Neoblasts can be sorted into many “classes.” For example, one class of neoblasts contains all the materials to make skin cells, and others have the necessary toolkit to form the worms’ primitive kidneys or their intestines. According to the hierarchical model, these specialized neoblasts are intermediaries between a pluripotent cell at the top of the hierarchy, and the non-dividing body cells.

“You can imagine that the special cell at the top is a blank slate with no predisposition towards any cell type — it can make anything,” says Raz. “This is how we’ve often imagined development works.”

But Raz, Reddien and Omri Wurtzel, a former postdoc in the Reddien lab now at Tel Aviv University, started to question this assumption after noticing a few mysterious properties of planarian cells.

First of all, researchers have observed in the past that when a planarian is treated with radiation to kill all existing stem cells, a single neoblast can rescue the animal by forming a colony containing many different classes of neoblasts. If, as previous theories suggested, there was a single class of neoblast that gave rise to all these types, Raz and Reddien reasoned that that class should be a common resident in every colony that formed. After creating many of these colonies and analyzing their composition, however, the researchers saw that this was not the case. “For every class we looked at, there were plenty of colonies that lacked that class altogether,” says Reddien. “There was no unique class present in all colonies.”

Another sticking point: the researchers began to realize that, when applying the hierarchy model, the math of planarian cell divisions and potency just didn’t add up. In a prior cell transplantation study, the Reddien lab found that many of the neoblasts they tested were pluripotent —in this study they found that proportion to be larger than what they would expect if only non-specialized neoblasts were pluripotent. “When you add up all the different kinds of specialized neoblasts, it’s at least three quarters of the neoblast population, and almost certainly higher than that.” says Raz. Therefore, the researchers wondered if some specialized neoblasts could be pluripotent as well.

Another study from the Reddien lab showed that skin-specialized neoblasts did not retain skin fate through more than one cell division. Also, in about half of all cell divisions in planarians, the two daughter cells will be different from one another. This raised the possibility that specialized neoblasts can divide asymmetrically as a possible route to stem cells changing fate.

Furthermore, the timeline for regeneration was off — the rate at which planarians were able to regrow body parts didn’t allow for several rounds of fate-restricting divisions.

After conducting experiments to study these different situations, Raz, Wurtzel, and Reddien were able to create a case for their new model of cell differentiation. “What we think is happening is that planarians have a ton of plasticity in their general stem cell population, where individual cells can move in and out of different specialized stages through the process of cell division in order to give rise to what is required,” Raz says.

“This is just the beginning of exploring this process, even though we’ve been studying it for many years,” Reddien says. “Focusing on the model, we’re suggesting that the cells can choose one fate, and then through the process of a division with an asymmetric outcome, one of the daughter cells can now divide again and choose a different fate. That fate switching process might be fundamental to explaining pluripotency.”

Reddien’s lab will continue investigating the mechanisms of neoblast fate specification, including how specialization lines up with the timing of the cell cycle.

“Understanding the structure of cell lineage and how fate choices are made is fundamental to understanding adult stem cell biology, and how in the context of injury and repair, new cells can be brought about,” says Reddien. “Do they have to go through long, complex lineage trajectories? Or can they make big jumps in state from stem cells to the final state? How flexible is that? All of these things have potential implications for understanding stem cell biology broadly, and we hope that the work will highlight some of these mechanisms and provide opportunities to explore general principles in the future.”

Intrigued by immortality
Eva Frederick | Whitehead Institute
March 16, 2021

New Whitehead Institute director Ruth Lehmann and new Member Yukiko Yamashita study opposite sides of the germ cell life cycle. Yamashita’s work in male germ cells shows how the cells are formed and maintained; Lehmann studies female germ cells to understand their fates. At the Whitehead Institute, they join Member and former director David Page in painting a fuller picture of how these seemingly immortal cell lines pass instructions uninterrupted from generation to generation.

All other cells in the body — neurons, muscle cells, the stem cells that replenish other tissue types — are made anew in each embryo and go away when organisms die. But not the germ cells. “The germ cell passes its DNA to the next generation, then that DNA is used to build up to a new germ cell,” says Yamashita. “That means that germ cells never cease to exist.”

In this way, an unbroken chain of germ cells stretches back to our most distant ancestor. Scientists study this never-ending link for insights into the fundamentals of biology and evolution. Yamashita began studying germ cells as a model to investigate other questions, but as her research progressed, she grew more and more intrigued by the cells’ special properties.

“This is one thing Ruth and I have in common,” Yamashita says. “There are many biologists that study germ cells, but not many are acutely interested or fascinated by this immortality. We want to know, where does it come from?”

Yamashita, also an Investigator of the Howard Hughes Medical Institute, joined Whitehead Institute in September. Work in her laboratory at Whitehead Institute will focus on two areas, using the fruit fly Drosophila melanogaster as a model. First, she will continue her focus from previous projects on the mechanics of asymmetric cell division using male germline stem cells. These cells, like other stem cells in the body, must undergo a series of asymmetric divisions — instead of simply dividing into two identical daughter cells, the cells must create daughters with different cell fates and programming.

“This balance — maintaining the stem cell number while making some differentiating cells — is considered to be a very important process,” she says. “If you end up making too many stem cells, it can become cancerous; but if you commit too much to the differentiation, you lose the stem cell count, and that means you cannot continue sperm production.”

A newer project in her lab centers on the long sequences of nucleotides within organisms’ genomes that don’t code for any genes. They’re often nonsensical, gibberish combinations or long strings of certain bases. This “genomic junk” has long been dismissed as meaningless filler between essential genes, but Yamashita proposes that the junk is essential for the overall structure of the genome. Much like the binding of a book holds together its contents in an organized fashion, the genomic junk may provide a blueprint for how genetic material is held together and eventually read.

Ultimately, it is the germline cells that are responsible for maintaining this DNA framework. Yamashita hypothesizes that slow changes in junk DNA could provide some explanation for why different species are reproductively incompatible.

“If you look at the chimpanzee genome and the human genome, the protein coding regions are, like, 98 percent, 99 percent identical,” she says. “But the junk DNA part is very, very different. We think this divergence might explain what happens when one species splits into two.”

Yamashita’s research team will share lab space with Lehmann’s group. Both researchers use fruit flies for their experiments, but Lehmann’s research focuses on egg cells, not sperm. “Germ cells are special; you don’t need them for survival, but you need them to keep the species going,” she says. “How are they initially specified and set aside? What makes them different, how are they set aside from somatic cells, and how do they maintain their cell fate?”

One project Lehmann is carrying over from her work at New York University’s Skirball Institute of Biomolecular Medicine involves phase transition condensates — small, membraneless granules that bring together the components needed for complex cellular functions. Lehmann studies a specific type of condensate called a germ granule, an aggregation of small RNAs and RNA binding proteins found only in germline cells, which helps determine the cells’ fate.

Lehmann is also investigating the female germline cells’ role in maternal inheritance. After fertilization, the maternal cell imparts not only its nuclear DNA but also components of its cytoplasm, including mitochondria, RNAs, and even bacteria. “This whole idea of cytoplasmic inheritance and the transgenerational continuum of the cytoplasm is something I’m just starting to think about,” she says.

Yamashita and Lehmann share a large open space on the third floor of the Institute, with researchers from each lab integrated throughout. They will also share a fly room and computational room. The researchers hope the communal setup will allow a flow of ideas between their labs. “By sharing this kind of basic space, we are hoping to let our people interact with each other and for discussions to happen,” Yamashita says.

“This is a new concept for Whitehead, and we’ll see how it works,” Lehmann says. “It’s an exciting experiment in lab sociology.”

Study reveals how egg cells get so big

Oocyte growth relies on physical phenomena that drive smaller cells to dump their contents into a larger cell.

Anne Trafton | MIT News Office
March 10, 2021

Egg cells are by far the largest cells produced by most organisms. In humans, they are several times larger than a typical body cell and about 10,000 times larger than sperm cells.

There’s a reason why egg cells, or oocytes, are so big: They need to accumulate enough nutrients to support a growing embryo after fertilization, plus mitochondria to power all of that growth. However, biologists don’t yet understand the full picture of how egg cells become so large.

A new study in fruit flies, by a team of MIT biologists and mathematicians, reveals that the process through which the oocyte grows significantly and rapidly before fertilization relies on physical phenomena analogous to the exchange of gases between balloons of different sizes. Specifically, the researchers showed that “nurse cells” surrounding the much larger oocyte dump their contents into the larger cell, just as air flows from a smaller balloon into a larger one when they are connected by small tubes in an experimental setup.

“The study shows how physics and biology come together, and how nature can use physical processes to create this robust mechanism,” says Jörn Dunkel, an MIT associate professor of physical applied mathematics. “If you want to develop as an embryo, one of the goals is to make things very reproducible, and physics provides a very robust way of achieving certain transport processes.”

Dunkel and Adam Martin, an MIT associate professor of biology, are the senior authors of the paper, which appears this week in the Proceedings of the National Academy of Sciences. The study’s lead authors are postdoc Jasmin Imran Alsous and graduate student Nicolas Romeo. Jonathan Jackson, a Harvard University graduate student, and Frank Mason, a research assistant professor at Vanderbilt University School of Medicine, are also authors of the paper.

A physical process

In female fruit flies, eggs develop within cell clusters known as cysts. An immature oocyte undergoes four cycles of cell division to produce one egg cell and 15 nurse cells. However, the cell separation is incomplete, and each cell remains connected to the others by narrow channels that act as valves that allow material to pass between cells.

Members of Martin’s lab began studying this process because of their longstanding interest in myosin, a class of proteins that can act as motors and help muscle cells contract. Imran Alsous performed high-resolution, live imaging of egg formation in fruit flies and found that myosin does indeed play a role, but only in the second phase of the transport process. During the earliest phase, the researchers were puzzled to see that the cells did not appear to be increasing their contractility at all, suggesting that a mechanism other than “squeezing” was initiating the transport.

“The two phases are strikingly obvious,” Martin says. “After we saw this, we were mystified, because there’s really not a change in myosin associated with the onset of this process, which is what we were expecting to see.”

cluster of cells

Martin and his lab then joined forces with Dunkel, who studies the physics of soft surfaces and flowing matter. Dunkel and Romeo wondered if the cells might be behaving the same way that balloons of different sizes behave when they are connected. While one might expect that the larger balloon would leak air to the smaller until they are the same size, what actually happens is that air flows from the smaller to the larger.

This happens because the smaller balloon, which has greater curvature, experiences more surface tension, and therefore higher pressure, than the larger balloon. Air is therefore forced out of the smaller balloon and into the larger one. “It’s counterintuitive, but it’s a very robust process,” Dunkel says.

Adapting mathematical equations that had already been derived to explain this “two-balloon effect,” the researchers came up with a model that describes how cell contents are transferred from the 15 small nurse cells to the large oocyte, based on their sizes and their connections to each other. The nurse cells in the layer closest to the oocyte transfer their contents first, followed by the cells in more distant layers.

“After I spent some time building a more complicated model to explain the 16-cell problem, we realized that the simulation of the simpler 16-balloon system looked very much like the 16-cell network. It is surprising to see that such counterintuitive but mathematically simple ideas describe the process so well,” Romeo says.

The first phase of nurse cell dumping appears to coincide with when the channels connecting the cells become large enough for cytoplasm to move through them. Once the nurse cells shrink to about 25 percent of their original size, leaving them only slightly larger than their nuclei, the second phase of the process is triggered and myosin contractions force the remaining contents of the nurse cells into the egg cell.

“In the first part of the process, there’s very little squeezing going on, and the cells just shrink uniformly. Then this second process kicks in toward the end where you start to get more active squeezing, or peristalsis-like deformations of the cell, that complete the dumping process,” Martin says.

Cell cooperation

The findings demonstrate how cells can coordinate their behavior, using both biological and physical mechanisms, to bring about tissue-level behavior, Imran Alsous says.

“Here, you have several nurse cells whose job it is to nurse the future egg cell, and to do so, these cells appear to transport their contents in a coordinated and directional manner to the oocyte,” she says.

Oocyte and early embryonic development in fruit flies and other invertebrates bears some similarities to those of mammals, but it’s unknown if the same mechanism of egg cell growth might be seen in humans or other mammals, the researchers say.

“There’s evidence in mice that the oocyte develops as a cyst with other interconnected cells, and that there is some transport between them, but we don’t know if the mechanisms that we’re seeing here operate in mammals,” Martin says.

The researchers are now studying what triggers the second, myosin-powered phase of the dumping process to start. They are also investigating how changes to the original sizes of the nurse cells might affect egg formation.

The research was funded by the National Institute of General Medical Sciences, a Complex Systems Scholar Award from the James S. McDonnell Foundation, and the Robert E. Collins Distinguished Scholarship Fund.

Proteins and labs come together to prevent Rett syndrome
Greta Friar | Whitehead Institute
July 22, 2020

New discoveries about the disruption of condensates in the neurodevelopmental disorder Rett syndrome provide insights into how cells compartmentalize chromosomes as well as new potential paths for therapies.

Scientists have, for many years, conceptualized the cell as a relatively free-flowing space, where–apart from the organization provided by specific cellular structures–molecules float freely, somehow ultimately ending up in the right place at the right time. In recent years, however, scientists have discovered that cells have much more spatial organization than previously thought thanks to a mechanism called phase separation, which occurs in cells when certain molecules form large droplet-like structures that separate what’s inside of the droplet from the rest of the cell. The droplets, called condensates, help sequester and concentrate molecules in specific locations, and appear to increase the efficiency of certain cellular functions.

Whitehead Institute Member Richard Young, also a professor of biology at Massachusetts Institute of Technology (MIT), has been exploring the previously unknown role that condensates play in gathering the molecules needed for gene transcription–the process by which DNA is read into RNA. In order to better understand when and how cells use phase separation, Charles Li, a graduate student in Young’s lab, set out to identify more proteins that can form condensates. That search led him to MeCP2, a protein associated with the severe neurodevelopmental disorder Rett syndrome, studied by Young’s colleague at Whitehead Institute, Founding Member Rudolf Jaenisch, who is also a professor of biology at MIT. No cure for Rett syndrome currently exists, and Jaenisch’s lab has been investigating the biology of the disorder in the hopes of discovering a medical therapy that can rescue neurons affected by Rett syndrome.

With the discovery of MeCP2’s condensate forming ability, Young and Jaenisch saw the opportunity for a promising collaboration between their labs. Led by co-first authors Li and Eliot Coffey, another graduate student in Young’s lab, the two labs investigated MeCP2 and whether the disruption of its condensate-forming ability contributes to Rett syndrome. During these investigations, the researchers also uncovered how cells may use condensates to help organize the active and inactive parts of chromosomes. Their findings, published in the journal Nature on June 22, report on these insights and suggest new paths for developing therapies for Rett syndrome.

PHASE SEPARATION AND RETT SYNDROME

Proteins that form condensates often contain intrinsically disordered regions (IDRs), long spaghetti-like strands that transiently stick together to form a dynamic mesh. Research has historically focused on the structured regions of proteins, which bind very specifically to other molecules, while IDRs have largely been overlooked. In this case, MeCP2’s large IDRs were exactly what drew Li to it.

“What was striking to me was that this protein has been studied for decades, and so much function has been ascribed to the protein as a whole, yet it only has one structured domain with a recognized function, the DNA binding domain. Beyond that, the entire protein is disordered, and how its parts function was largely unknown,” Li says.

The researchers found that MeCP2 used its IDRs to glom together and form condensates. Then they tested many of the mutations in the MECP2 gene that are associated with Rett syndrome and found that they all disrupt MeCP2’s ability to form condensates. Their findings suggest that therapies targeting condensates associated with the protein, rather than the protein itself, may be promising in the hunt for a Rett syndrome treatment.

“MeCP2 and Rett syndrome have been studied intensely for many years in many labs and yet not a single therapy has been developed. When the project began, I was immediately fascinated by the idea that we might find a new disease mechanism that could help us finally understand how Rett syndrome arises and how it could be treated,” Coffey says.

“Rick [Young] has shown that condensates play key roles in maintaining normal cellular function, and our latest collaboration illuminates how their disruption may drive diseases such as Rett syndrome,” Jaenisch says. “I hope the insights we have gained will prove useful both in our continued search for a treatment for Rett syndrome and more broadly in research on condensates and disease.”

COMPARTMENTALIZING CHROMOSOMES

The researchers’ investigation into MeCP2’s condensate forming behavior also shed light on how chromosomes are organized into regions of active and inactive genes. When MeCP2 is functioning normally, it helps to maintain heterochromatin, the roughly half of our chromosomes where genes are “turned off,” unable to be read into RNA or further processed to make proteins. MeCP2 binds to sequences of DNA marked with a certain type of regulatory tag that is typically found in heterochromatin. This helps crowd MeCP2 to the threshold concentration needed to form heterochromatin condensates. These condensates, in turn, help to sequester the molecules needed to maintain it apart from euchromatin, the half of our chromosomes filled with active genes. Different proteins form condensates near euchromatin, concentrating the molecular machinery needed to transcribe active genes there.

Since condensates form when proteins with large spaghetti-like IDRs stick together, one might expect that any protein containing IDRs could interact with any other IDR-containing protein to form droplets, and that is what the researchers have often seen. However, what they observed with MeCP2, which is associated with heterochromatin, is that key condensate-forming proteins associated with euchromatin refused to mix.

It’s important for the health of the cell that the genes in heterochromatin not be inadvertently turned on. The researchers reason that discrete euchromatin and heterochromatin condensates may play a key role in ensuring that transcriptional machinery localizes to euchromatin only, while repressive machinery–like MeCP2–localizes to heterochromatin. The researchers are excited to turn their attention to how proteins are able to join condensates selectively, and when and where else in the cell they do so.

“There’s a chemical grammar waiting to be deciphered that explains this difference in the ability of some proteins to move into one condensate versus another,” Young says. “Discovering that grammar can help us understand how cells maintain the crucial balance between the active and silent halves of our genome, and it could help us understand how to treat disorders such as Rett syndrome.”

***

Written by Greta Friar

Richard Young’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at the Massachusetts Institute of Technology.

Rudolf Jaenisch’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Li, C.H., Coffey, E., et al. (2020). MeCP2 links heterochromatin condensates and neurodevelopmental disease. Nature. DOI: 10.1038/s41586-020-2574-4

Yukiko Yamashita

Education

  • PhD, 1999, Kyoto University
  • BS, Biology, 1994, Kyoto University

Research Summary

Two remarkable feats of multicellular organisms are generation of many distinct cell types via asymmetric cell division and transmission of the germline genome to the next generation, essentially in eternity. Studying these processes using the Drosophila male germline as a model system has led us to venture into new areas of study, such as functions of satellite DNA, a ‘genomic junk,’ and how they might be involved in speciation.

Awards

  • Tsuneko and Reiji Okazaki Award, 2016
  • Howard Hughes Medical Institute, Investigator, 2014
  • MacArthur Fellow, 2011
  • Women in Cell Biology Early Career Award, American Society for Cell Biology, 2009
  • Searle Scholar, 2008
Ruth Lehmann

Education

  • Dr. rer. nat., 1985, University of Tübingen
  • MS, 1981, Biology, University of Freiburg

Research Summary

We study germ cells, the only cells in the body naturally able to generate completely new organisms. In addition to the nuclear genome, cytoplasmic information is passed though the egg cell to the next generation. We analyze the organization and regulation of germ line specific RNA-protein condensates, and explore mechanisms used by endosymbionts such as mitochondria and the intracellular bacterium, Wolbachia, to propagate through the cytoplasm of the female germ line.

Awards

  • Vanderbilt Prize in Biomedical Science, 2022
  • Gruber Genetics Prize, 2022
  • Thomas Hunt Morgan Medal, Genetics Society of America, 2021
  • Francis Amory Prize in Reproductive Medicine and Reproductive Physiology, American Academy of Arts and Sciences, 2020
  • Vilcek Prize in Biomedical Science, 2020
  • Keith R. Porter Award, American Society for Cell Biology, 2018
  • Inaugural Klaus Sander Prize, German Society for Developmental Biology, 2017
  • European Molecular Biology Organization, Foreign Associate, 2012
  • Conklin Medal of the Society of Developmental Biology, 2011
  • National Academy of Sciences, Foreign Associate, 2005; Member, 2008
  • American Academy of Arts and Sciences, Member, 1998
  • Howard Hughes Medical Institute, Investigator, 1990 and 1997
These muscle cells are guideposts to help regenerative flatworms grow back their eyes
Eva Frederick | Whitehead Institute
June 25, 2020

If anything happens to the eyes of the tiny, freshwater-dwelling planarian Schmidtea mediterranea, they can grow them back within just a few days. How they do this is a scientific conundrum — one that Peter Reddien’s lab at Whitehead Institute has been studying for years.

The lab’s latest project offers some insight: in a paper published in Science June 25, researchers in Reddien’s lab have identified a new type of cell that likely serves as a guidepost to help route axons from the eyes to the brain as the worms complete the difficult task of regrowing their neural circuitry.

Schmidtea mediterranea’s eyes are composed of light-capturing photoreceptor neurons connected to the brain with long, spindly processes called axons. They use their eyes to respond to light to help navigate their environment.

The worms, which are popular models for research into regeneration, can regrow pretty much any part of their body; eyes are an interesting part to study because regenerating the visual system requires the worms rewire their neurons to connect them to the brain.

When neural systems develop in embryos, the first nerve fibers, called pioneer axons, snake their way through tissue to form the circuitry needed to perceive and interpret external stimuli. The axons are helped along their way by specialized cells called guidepost cells. These special cells are positioned at choice points — places where the axon’s path could fork in different directions.

In many organisms, these guidepost cells aren’t a priority anymore once development is finished, and typically are not renewed through adulthood. That’s one reason why, when humans experience brain or nerve damage, the injury is usually permanent.

“This is a fundamental mystery of regeneration that we hadn’t even been thinking about,” says Reddien, the senior author of the paper who is also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute. “How can an adult animal regenerate a functional nervous system when the original development of the nervous system typically involves a number of cues that are thought to be transient?”

Then, in 2018, Reddien Lab scientist Lucila Scimone found something surprising in adult planarians: groups of mysterious cells that looked like they might play a role in guiding growing axons. She’d noticed this group of cells because they co-expressed two genes not often seen together and some were conspicuously close to the eyes.

“I was captivated by these cells,” she says. They appeared in very small numbers (a normal worm might have around 5; a large one might have up to 10) in every planarian she examined. They were divided into two distinct groups: some around the flatworms’ eyes, and others spaced out along the path to the brain center. When she traced the path of existing axons leading from the planarians’ eyes to their brain, they coincided with the positions of these cells without exception.

When the researchers characterized the cells, they found that they did not express any of the genes that are hallmarks of photoreceptor neurons; instead, they had markers often found in muscle tissue. “That was very striking, because muscle cells — that’s not what they do in most animals,” Scimone says.

In other organisms, guidepost cells are often neurons or glia. It would be unusual for muscle cells to serve as guideposts; but past work in the Reddien Lab had shown that planarian muscle cells played other special roles, such as secreting the extracellular matrix. The researchers now wondered whether they could add the role of guidepost to the long list of planarian muscle cell functions.

To test their hypothesis, the researchers designed a series of experiments. “We developed an eye transplantation method where you can take an eye from an animal and transplant it into another animal,” says Reddien Lab postdoc Kutay Deniz Atabay. “When you do this, the axonal projections from that eye will basically, if positioned appropriately, correctly wire themselves into the brain, producing a functional state.”

The researchers also created genetically engineered planarians that had the muscle cells, but no eyes, and then transplanted eyes onto their eyeless heads. Sure enough, the neurons grew as normal, snaking towards the cells and then adjusting their trajectories after encountering them.

Without the cells, it was a different story. When the researchers transplanted eyes to distant parts of planarians’ bodies without a population of these muscle cells, the photoreceptor neurons did not connect to the brain center. Likewise, when they transplanted eyes into planarians that had been modified to not have these muscle cells, their photoreceptor neurons still grew — but they did not wire properly to reach the brain.

These findings combined suggested that the cells were fully independent of the visual system — they did not form because of eyes or photoreceptor neurons, but likely established themselves before the neurons grew — which provided more evidence for the guidepost role.

The guidepost-like activity of these cells then begged the question: how do the cells themselves know where to be? “We found that there’s a pattern of signaling molecules in muscle that is setting where these cells should be,” Reddien says. “If we perturb the global positional information of the system, these cells get placed in the wrong positions, and then axons go to the wrong positions — so we think there’s a positional information framework that places the cells during regeneration, and that allows them to work as guideposts in the correct locations.”

At this point, the researchers don’t know exactly how the cells are able to communicate with growing axons to serve as guideposts. They could be releasing some sort of signaling molecule that attracts the axons, or they could be communicating by using trans-membrane proteins.

“That will be an exciting direction for the future,” Reddien says. “We have now identified the transcriptome for the cells, which means we know all the genes that these cells express. That provides us with an intriguing list of genes that can be probed functionally, to try to see which ones are mediating the functions of these cells.”

This study is a step forward in a body of work that aims to expand the capabilities of regenerative medicine. “Imagine a scenario where someone experiences a spinal cord injury or an eye injury or stroke that leads to the loss of a neural circuit,” says Atabay. “The reason we can’t fully cure these cases today is that we lack fundamental information regarding how these systems can regenerate. Looking at regenerative organisms provides a lot of insights. From this case, we see that regenerating the lost system may not be enough; you may also need to regenerate systems that are properly patterning that system.”

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Written by Eva Frederick

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Scimone, M. L. et al. “Muscle and neuronal guidepost-like cells facilitate planarian visual system regeneration.” Science, June 25, 2020.