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Calcium triggers stem cells to generate bone

Calcium is the main constituent of bone, and now is found to play a major role in regulating its growth. This new finding may affect treatment of conditions caused by too much collagen, such as fibrosis which thickens and scars connective tissue, as well in diseases of too little bone growth, such as Treacher Collins Syndrome (TCS).

Michael Rape and his colleagues at the University of California, Berkeley, followed cell signals in the very early embryo as they alert undifferentiated stem cells to become specialized cells. They then followed those signals to unravel the craniofacial disorder Treacher Collins Syndrome, TCS.

In the embryo, TCS cannot form a structure called the neural crest, from which the jaw, inner ear and numerous bones in the head and face develop. As a result, people like Francis Smith, a 41-year-old University of Colorado researcher, required dozens of surgeries during childhood to reconstruct his face, implant hearing aids and even reconstruct his trachea so he could breathe normally. Smith visited Rape in his lab a month ago.

After the visit, Rape hopes his basic research can identify key signals that trigger proper bone growth. This in order to help embryonic bones grow, and help people with TCS avoid painful surgeries. One option might be implanting a biodegradable matrix seeded with bone cells called chondrocytes, in areas missing the signals expected. Perhaps then the seeded matrix could be stimulated to release collagen, the blueprint for bone growth, as Rape's findings suggest calcium would trigger bone growth.

"You would basically add calcium to cells on those support structures, which is fairly easy, and motivate chondrocytes to secrete the collagen needed to build a bone structure on top of that support. That would be exciting, but it is very much in the future. Nevertheless, this might become a possibility the more we understand about how cells make their decisions."

Michael Rape PhD, the Dr. K. Peter Hirth Chair of Cancer Biology and Professor of Cell and Developmental Biology at the University of California, Berkeley.

The finding might also explain how interrupting the body's calcium levels during pregnancy may cause facial deformities such as those associated with fetal alcohol syndrome.

Rape and his colleagues reported their results online October 6, 2016 in the journal Cell.

Using a unique screening process he developed, Rape attaches ubiquitin protein to proteins inside stem cells. Ubiquitin drives undifferentiated cells toward a specific fate. One molecule of ubiquitin often forces a pluripotent stem cell to become a collagen-producing chondrocyte.

Enzymes that attach a chain of ubiquitin molecules to a protein — target that protein for destruction and recycling.

The Nobel Prize in Physiology or Medicine, 2016, was awarded to Yoshinori Ohsumi of Tokyo Institute of Technology's Frontier Research Center for his discovery of this type of autophagy.

Last year, Rape's lab identified an enzyme, called CUL3, that adds ubiquitin to the TCOF1 protein and makes stem cells mature into neural crest cells. When both copies of TCOF1 are mutated, the embryo dies.

But if only one of the two copies of TCOF1 is mutated, as in TCS, fewer neural crest cells are produced and many die early, leading to improper bone growth in the skull.

Other studies have shown that CUL3 acts at many stages of human development.

Problems with regulation of CUL3 have been associated with autism, schizophrenia, myopathy and hypertension.

In his new experiments, Rape searched for the signals that turn on ubiquitylation enzymes like CUL3, allowing the developing embryo to form bone at the right time and in the right place in the organism. He found that CUL3 needs the help of two calcium-binding proteins, which was a surprise.

"Our research basically identifies calcium not only as a structural element of bone, which makes the bone strong and sturdy, but also as a signaling molecule for bone formation that we hadn't appreciated before, which can be used to turn enzymes on and off," he said. "Calcium is a very important regulatory molecule that allows the organism to make cell-fate decisions."

Because CUL3 not only triggers stem cells to become neural crest cells, but stimulates chondrocytes to secrete collagen, calcium evidently plays a major role in many aspects of bone formation.

"This means is that you basically have many different steps that come together in order to form a bone, and that they are beautifully orchestrated by calcium.

"Calcium is really a sort of integrating signal, which is there at the right time and place to set in motion a whole series of reactions to build bone where it should be built.

"It is a very elegant idea that you don't need a lot of different signals to come together, but one that really pops into the right sequence of events."

Michael Rape PhD

Further research is needed, however, before physicians can attempt regenerative therapies to help TCS patients like Smith.

"The more you understand about each of these steps, the easier it is to focus your applied research onto things that matter and change something for these patients," Rape said.

Abstract Highlights
•PEF1 and ALG2 are novel subunits of the CUL3KLHL12 ubiquitin ligase
•PEF1 and ALG2 control SEC31-ubiquitylation, COPII vesicle size, and collagen secretion
•PEF1 and ALG2 impose calcium regulation onto CUL3KLHL12
•Calcium-dependent control of CUL3KLHL12 regulates COPII vesicle size

The ubiquitin ligase CUL3 is an essential regulator of neural crest specification whose aberrant activation has been linked to autism, schizophrenia, and hypertension. CUL3 exerts its roles by pairing with ∼90 distinct substrate adaptors, yet how the different CUL3-complexes are activated is poorly understood. Here, we show that CUL3 and its adaptor KLHL12 require two calcium-binding proteins, PEF1 and ALG2, for recognition of their substrate SEC31. PEF1 and ALG2 form a target-specific co-adaptor that translates a transient rise in cytosolic calcium levels into more persistent SEC31 ubiquitylation, which in turn triggers formation of large COPII coats and promotes collagen secretion. As calcium also instructs chondrocyte differentiation and collagen synthesis, calcium-dependent control of CUL3KLHL12 integrates collagen secretion into broader programs of craniofacial bone formation. Our work, therefore, identifies both calcium and CUL3 co-adaptors as important regulators of ubiquitylation events that control human development.

Co-authors with Rape are UC Berkeley graduate students Colleen McGourty, Carolyn Walsh and Amita Gorur, postdocs David Akopian and Achim Werner, and molecular and cell biology professors Randy Schekman and Diana Bautista.

McGourty was supported by a predoctoral fellowship of the National Science Foundation. Walsh was a recipient of a fellowship from the California Institute of Regenerative Medicine. The work was in part funded in part by a basic biology grant from the California Institute of Medicine, and by the Howard Hughes Medical Institute.

ubiquitin, CUL3, endoplasmic reticulum, SEC31, calcium

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Oct 10, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Francis Smith was born with the craniofacial disorder Treacher Collins Syndrome. He met
with UC Berkeley researcher Michael Rape, who has discovered signaling molecules that
may help repair the disorder after birth.

Image Credit:
from a Video by Roxanne Makasdjian and Stephen McNally, Univ Cal at Berkeley.


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