A)Cell cycle speed is key to making aging cells young again
A fundamental axiom of biology used to be that cell fate is a one-way street — once a cell commits to becoming muscle, skin, or blood it always remains muscle, skin, or blood cell. That belief was upended in the past decade when a Japanese scientist introduced four simple factors into skin cells and returned them to an embryonic-like state, capable of becoming of almost any cell type in the body.
Hopeful of revolutionary medical therapies using a patient’s own cells, scientists rushed to capitalize on the discovery by 2012 Nobel Laureate Shinya Yamanaka. However, the process has remained slow and inefficient, and scientists have had a difficult time discovering a genetic explanation of why this should be.
In the Jan. 30 issue of the journal Cell, Yale School of Medicine researchers identified a major obstacle to converting cells back to their youthful state — the speed of the cell cycle, or the time required for a cell to divide.
When the cell cycle accelerates to a certain speed, the barriers that keep a cell’s fate on one path diminish. In such a state, cells are easily persuaded to change their identity and become pluripotent, or capable of becoming multiple cell types
“One analogy may be that when temperature increases to sufficient degrees, even a very hard piece of steel can be malleable so that you can give it a new shape easily,” said Shangqin Guo, assistant professor of cell biology at the Yale Stem Cell Center and lead author of the paper. “Once cells are cycling extremely fast, they do not seem to face the same barriers to becoming pluripotent.”
Guo’s team studied blood-forming cells, which when dividing undergo specific changes in their cell cycle to produce new blood cells. Blood-forming progenitor cells normally produce only new blood cells. However, the introduction of Yamanaka factors sometimes — but not always — help these blood-forming cells become other types of cells. The new report finds that after this treatment blood-forming cells tend to become pluripotent when the cell cycle is completed in eight hours or less, an unusual speed for adult cells. Cells that cycle more slowly remain blood cells.
“This discovery changes the way people think about how to change cell fate and reveals that a basic ‘house-keeping’ function of a cell, such as its cell cycle length, can actually have a major impact on switching the fate of a cell,” said Haifan Lin, director of the Yale Stem Cell Center.
The study has other implications than explaining the bottleneck in reprogramming that makes it difficult to produce individualized pluripotent stem cells for research and therapy. Shangqin Guo noted that many human diseases are associated with abnormalities in establishing proper cell identity as well as abnormalities in cell cycle behavior.
Other Yale-affiliated authors are Xiaoyuan Zi, Vincent Schulz, Jijun Cheng, Mei Zhong, Sebastian H.J. Koochaki, Cynthia M. Megyola, Xinghua Pan, Kartoosh Heydari, Sherman M. Weissman, Patrick G. Gallagher, Diane S. Krause, Rong Fan, and Jun Lu.
The research was funded by the National Institutes of Health and the Connecticut Stem Cell Research Program.
VIDEO LINK AT http://vimeo.com/59083655
B)Novel genes determine division of labor in insect societies
Mainz biologists show in a scientific study how gene expression differs between castes in ants
Novel or highly modified genes play a major role in the development of the different castes within ant colonies. Evolutionary biologists at Johannes Gutenberg University Mainz (JGU) came to this conclusion in a recent gene expression study. Dr. Barbara Feldmeyer and her colleagues at the JGU Institute of Zoology studied the question how the different female castes arise. An ant colony generally consists of a queen and the workers. Moreover, workers can differ depending on the task they perform, such as brood care, foraging, or nest defense. This behavioral specialization may be accompanied by morphological and physiological differences. Queens, solely responsible for reproduction, can live up to 30 years while workers have life spans ranging from a few months to several years. In some species there are also soldier ants, which can weigh up to 100 times more than their worker sisters who take care of the brood.
Interestingly, the divergent phenotypic traits of queens and workers develop from the same genetic background; the different phenotypic trajectories are determined by the food larvae receive during development. Usually the queen is the sole reproductive individual in a nest but if she dies or is removed, some brood-care workers will develop their ovaries and begin to reproduce. It was this phenomenon that the Mainz scientists exploited in order to induce fertility in brood-care workers of the Temnothorax longispinosus ant species. This allowed the comparison of these fertile workers with infertile brood-carers, foragers, and the queens to determine the expression of genes causing the enormous variations in behavior, fertility, and life span.
“We have here the ideal model system to study polyphenism, which describes the situation in which one and the same genotype gives rise to phenotypes that differ in terms of individual morphology, behavior, and life history,” said Dr. Barbara Feldmeyer. Each sample used for RNA sequencing encompassed up to 100 million reads, i.e., short sequence sections of about 100 base pairs. The largest differences in gene expression were found between the queen and the worker castes, while the smallest differences were determined between the infertile brood carers and the foragers. The fertile brood care workers occupy an intermediate position between the queen and the sterile workers.
The ant queens expressed many caste-specific genes whose functions were known from comparisons with other species. This is not the case for the workers in which about half of the characteristic genes were found to be of unknown function. “Either these worker genes have undergone major modifications or they are novel genes,” explained Feldmeyer. The fact that queens express more genes known from solitary hymenopterans and other insects fits to the evolution of social insects with workers being the derived state.
“This study of the differences in gene expression among ant castes is characteristic of the enormous advances that are currently being made in the field of biology,” explained Professor Susanne Foitzik, head of the Evolutionary Biology work group at Mainz University. RNA sequencing is a technique that enables scientists to gain in-depth molecular information even for organisms that are not among the standard biological model organisms, such as the fruit fly Drosophila. “We can now also look at species known for their complexity in social behavior. In addition, by studying ants we can gain insights into the genes that are responsible for the unusually long life and fertility in insect queens,” added Foitzik. The work group plans to continue its research into this area under the aegis of the new GeneRED research unit of the Faculty of Biology and the Institute of Molecular Biology (IMB).
C)Timing is everything: How the brain links memories of sequential events
January 23, 2014
Suppose you heard the sound of skidding tires, followed by a car crash. The next time you heard such a skid, you might cringe in fear, expecting a crash to follow — suggesting that somehow, your brain had linked those two memories so that a fairly innocuous sound provokes dread. Scientists have now discovered how two neural circuits in the brain work together to control the formation of such time-linked memories.
This cross-section of the hippocampus shows island cells (green) projecting to the CA1 region of the hippocampus.
Credit: Takashi Kitamura
Suppose you heard the sound of skidding tires, followed by a car crash. The next time you heard such a skid, you might cringe in fear, expecting a crash to follow — suggesting that somehow, your brain had linked those two memories so that a fairly innocuous sound provokes dread.
MIT neuroscientists have now discovered how two neural circuits in the brain work together to control the formation of such time-linked memories. This is a critical ability that helps the brain to determine when it needs to take action to defend against a potential threat, says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and senior author of a paper describing the findings in the Jan. 23 issue of Science.
“It’s important for us to be able to associate things that happen with some temporal gap,” says Tonegawa, who is a member of MIT’s Picower Institute for Learning and Memory. “For animals it is very useful to know what events they should associate, and what not to associate.”
The interaction of these two circuits allows the brain to maintain a balance between becoming too easily paralyzed with fear and being too careless, which could result in being caught off guard by a predator or other threat.
The paper’s lead authors are Picower Institute postdocs Takashi Kitamura and Michele Pignatelli.
Memories of events, known as episodic memories, always contain three elements — what, where, and when. Those memories are created in a brain structure called the hippocampus, which must coordinate each of these three elements.
To form episodic memories, the hippocampus also communicates with the region of the cerebral cortex just outside the hippocampus, known as the entorhinal cortex. The entorhinal cortex, which has several layers, receives sensory information, such as sights and sounds, from sensory processing areas of the brain and sends the information on to the hippocampus.
Previous research has revealed a great deal about how the brain links the place and object components of memory. Certain neurons in the hippocampus, known as place cells, are specialized to fire when an animal is in a specific location, and also when the animal is remembering that location. However, when it comes to associating objects and time, “our understanding has fallen behind,” Tonegawa says. “Something is known, but relatively little compared to the object-place mechanism.”
The new Science paper builds on a 2011 study from Tonegawa’s lab in which he identified a brain circuit necessary for mice to link memories of two events — a tone and a mild electric shock — that occur up to 20 seconds apart. This circuit connects layer 3 of the entorhinal cortex to the CA1 region of the hippocampus. When that circuit, known as the monosynaptic circuit, was disrupted, the animals did not learn to fear the tone.
In the new paper, the researchers report the discovery of a previously unknown circuit that suppresses the monosynaptic circuit. This signal originates in a type of excitatory neurons discovered in Tonegawa’s lab, dubbed “island cells” because they form circular clusters within layer 2. Those cells stimulate inhibitory neurons in CA1 that suppress the set of excitatory CA1 neurons that are activated by the monosynaptic circuit.
This circuit creates a counterbalance that limits the window of opportunity for two events to become linked. “This pathway might provide a mechanism for preventing constant learning of unimportant temporal associations,” says Michael Hasselmo, a professor of psychology at Boston University who was not part of the research team.
The findings are “an important demonstration of the functional role of different populations of neurons in entorhinal cortex that provide input to the hippocampus,” Hasselmo adds.
The researchers used optogenetics, a technology that allows specific populations of neurons to be turned on or off with light, to demonstrate the interplay of these two circuits.
In normal mice, the maximum time gap between events that can be linked is about 20 seconds, but the researchers could lengthen that period by either boosting activity of layer 3 cells or suppressing layer 2 island cells. Conversely, they could shorten the window of opportunity by inhibiting layer 3 cells or stimulating input from layer 2 island cells, which both result in turning down CA1 activity.
The researchers hypothesize that prolonged CA1 activity keeps the memory of the tone alive long enough so that it is still present when the shock takes place, allowing the two memories to be linked. They are now investigating whether CA1 neurons remain active throughout the entire gap between events.
The research was funded by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation.
- Takashi Kitamura, Michele Pignatelli, Junghyup Suh, Keigo Kohara, Atsushi Yoshiki, Kuniya Abe, and Susumu Tonegawa. Island Cells Control Temporal Association Memory. Science, 23 January 2014 DOI: 10.1126/science.1244634