Courtesy Lammerding Lab

Image of skeletal muscle fibers that have been generated in vitro using a novel 3-D encapsulation method. Magenta=myosin heavy chain; Turquoise=actin; Green=Lamin B1; Red=DNA

September 17, 2018

New Frontier in Nucleus Capabilities

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From middle school biology we were always taught that the nucleus is the “control center” of the cell, similar to how the brain is the control center of our own bodies. At first glance this makes a lot of sense, considering the nucleus contains DNA — the genetic code of life — and a good amount of the machinery that is required to transcribe this code into the proteins that make up our being. Despite this seemingly intuitive role of the nucleus, a recent study conducted by the Prof. Jan Lammerding, biomedical engineering, and post-doctoral fellow Tyler Kirby, suggests the nucleus may also act as a “mechano-sensor” in the cell. A mechano-sensor is a component of the cell that responds to physical stimuli in the environment of the cell, such as touch, charge, or temperature. Previously the role of mechano-sensor was credited entirely to cell membrane proteins.

The study conducted by Lammerding and Kirby focused on Emery-Dreifuss muscular dystrophy — a disease that affects one in every 3,500 males and causes weakness in the shoulders, upper arms, and lower legs. More specifically the pair studied the LMNA gene which encodes two proteins that make up the nucleus: nuclear lamins A and C. A mutation in the LMNA gene will cause dysfunction of the lamin A-C proteins.

“Lamin A-C proteins are a primary determinant of … structure, or the rigidity and mechanical properties of the nucleus. If you lack those proteins it makes the nucleus very soft, which in turn affects how it can respond to mechanical forces,” Kirby said.

Lammerding and Kirby investigated why, despite all of the cells in a body possessing a mutated LMNA gene, only skeletal and cardiac muscle cells displayed extensive signs of nuclear damage, thus expressing the disease’s observable traits. Their current hypothesis is that muscle cells are only affected because of the constant mechanical stress that they are put under every time you move your body.

How were researchers able to deduce that the nucleus was doing the sensing? “The way that people are now approaching it is to specifically disrupt the way that the nucleus is connected to the rest of the cell,” Kirby said. There are two methods that researchers are currently using. The first involves “Link” complexes, which transmit stimuli from the cytoskeleton — the outer supportive framework of each cell — to the nucleus.

According to Kirby, other groups have “genetically manipulated” cells so they no longer have the Link complex. Afterwards they tested if this affected functions in the nucleus. Kirby said that there is emerging evidence that suggests altering Link complexes does in fact affect nucleus function.

The second method mentioned by Kirby was to remove the nucleus from the rest of the cell and observe physical changes in the nucleus when force was applied.

Dr. Lammerding is optimistic about continued research on the nucleus as a mechano-sensor in cells. If further research supports the lab’s hypothesis, it could potentially change the way we conduct cell stimuli research.

As it pertains to the healthcare field, taking the nucleus into account when seeking to cure illnesses, might “open the door for novel therapeutic approaches for treating Emery-Dreifuss muscular dystrophy and other currently untreatable diseases.” Lammerding said.