Nav: Home

Voltage gated calcium channels 'read' electric patterns in embryos to create cartilage and bone

October 07, 2019

MEDFORD/SOMERVILLE, Mass. (October 7, 2019)--Scientists at Allen Discovery Center at Tufts University and Harvard Medical School have revealed how, in the case of limb formation, the electrical patterns formed within an embryo initiate a cascade of molecular changes that culminate in the development of cartilage and bone. The study, published today in Proceedings of the National Academy of Sciences (PNAS), helps answer a central question in developmental biology: "How do immature cells in the developing embryo differentiate and organize into a body?"

Prior studies have shown remarkable electrical patterns in developing embryos, some of which act like blueprints of the tissues and organs that eventually take shape as the embryo matures. The electrical patterns are created by cells pumping charged ions into and out of the cell membrane, creating a voltage potential across the membrane barrier. In analogy to cells of the nervous system, the membrane voltage potentials spread via electrical synapses and provide a way for cells to communicate with their neighbors and coordinate activity.

The new study, conducted in mouse and chicken embryos, demonstrates that a voltage gated calcium channel (VGCC) embedded in the cell membrane, and triggered by voltage to allow calcium ions (Ca2+) to flow into the cell, sets off the expression of genes that guide differentiation to mature cells.

Voltage gated ion channels are known to have a role in the formation of tracheal cartilage, and mutations in VGCCs are also correlated with malformations in humans, including syndactyly (fusion of fingers) in Timothy syndrome patients. The study now points to a role for VGCCs in 'reading out' the bioelectric patterns of an embryo to set the genetic and protein expression machinery in play for body development.

The researchers looked at the developing limbs of both mice and chicken embryos and found that while the limb bud is initially hyperpolarized, with 1000-fold more calcium ions outside cells than inside, the core of the growing limb becomes depolarized as cartilage forms; (calcium ions flow into the cells to neutralize voltage). They found that the depolarization is mediated by VGCCs, allowing calcium ions to flow inward, which in turn activate a genetic transcription factor called NFATc1, which in turn initiates expression of other genes required for differentiation into mature cartilage cells. The VCGG studied (Cav1.2) was found to be essential for normal cartilage formation, while NFATc1 was confirmed to promote the differentiation of cartilage cells in vitro.

Looking at the role of Cav1.2 more closely, the researchers discovered that it primarily plays a part in the early stages of cell differentiation into cartilage. Other VGCCs may be involved at later stages of development, and other transcription factors may be activated by the increase in intracellular calcium during the process of cartilage and bone formation, according to the researchers.

"It's clear that while we have discovered an essential role for voltage gated calcium channels in reading the embryo's bioelectric pattern, we will need to continue work to understand the role of many different ion channels and genetic factors throughout all stages of development," said Cliff Tabin, associate of the Allen Discovery Center at Tufts and chairman of the Depertment of Genetics in the Blavatnik Institute at Harvard Medical School.

"We are just beginning to understand how the 'software' of embryonic development (the electrical patterns) are created and interpreted by the 'hardware' (the cells' genes and proteins) to enable the cells to cooperate and organize into a highly-patterned body," said Michael Levin, Vannevar Bush Professor of Biology in the School of Arts & Sciences and director of the Allen Discovery Center at Tufts. "Our collaboration with the genetics team in the Tabin lab extends this field to a very important model, the vertebrate limb, and is a great demonstration of how we get to a better understanding of physics in biology."
Other authors of the study are: Yuji Atsuta, first author and post-doctoral fellow, and Reiko Tomizawa, research technician, both in the Tabin lab.

This work was supported by the Allen Discovery Center program through The Paul G. Allen Frontiers Group and National Institutes of Health grant HD03443. Atsuta is a recipient of fellowships of the Naito Foundation and the Japan Society for the Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Atsuta, Y., Tomizawa, R.R., Levin, M. and Tabin, C.J. "L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development." PNAS (October 2019); DOI: (DOI number)

About Tufts University

Tufts University, located on campuses in Boston, Medford/Somerville and Grafton, Massachusetts, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

Tufts University

Related Cartilage Articles:

Can magnetic stem cells improve cartilage repair?
Cells equipped with superparamagnetic iron oxide nanoparticles (SPIOs) can be directed to a specific location by an external magnetic field, which is beneficial for tissue repair.
Common conditions keep many patients out of knee cartilage research studies
Issues like age or existing arthritis may preclude patients from participating in clinical studies for new therapies that could benefit them
Will MSC micropellets outperform single cells for cartilage regeneration?
Repair of cartilage injuries or defects is aided by the introduction of mesenchymal stem cells (MSCs), which can be incorporated into hydrogels to amplify their effects.
Exercise helps prevent cartilage damage caused by arthritis
Exercise helps to prevent the degradation of cartilage caused by osteoarthritis, according to a new study from Queen Mary University of London.
Cartilage could be key to safe 'structural batteries'
Your knees and your smartphone battery have some surprisingly similar needs, a University of Michigan professor has discovered, and that new insight has led to a 'structural battery' prototype that incorporates a cartilage-like material to make the batteries highly durable and easy to shape.
Potential arthritis treatment prevents cartilage breakdown
In an advance that could improve the treatment options available for osteoarthritis, MIT engineers have designed a new material that can administer drugs directly to the cartilage.
A hydrogel that adheres firmly to cartilage and meniscus
EPFL researchers have developed a hydrogel -- made up of nearly 90 percent water -- that naturally adheres to soft tissue like cartilage and the meniscus.
A joint effort to understand cartilage development
Anyone with arthritis can appreciate how useful it would be if scientists could grow cartilage in the lab.
Basel researchers succeed in cultivating cartilage from stem cells
Stable joint cartilage can be produced from adult stem cells originating from bone marrow.
Flaxseed-like particles can now grow bone, cartilage tissues for humans
Human stem cells have shown potential in medicine as they can transform into various specialized cell types such as bone and cartilage cells.
More Cartilage News and Cartilage Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at