Nav: Home

For the first time, scientists 'see' dual-layered scaffolding of cellular nuclei

February 11, 2019

PITTSBURGH, Feb. 11, 2019 - Our cells sometimes have to squeeze through pretty tight spaces. And when they do, the nuclei inside must go along for the ride. Using super-sensitive microscopic imaging, a team of scientists from the University of Pittsburgh and Carnegie Mellon University have made a fundamental biological discovery that explains the structure of the nuclear envelope and gives tantalizing clues as to how cells squish through narrow openings without springing a leak.

The findings, which also could be key to untangling the mechanisms underlying several genetic diseases, are described today in the Proceedings of the National Academy of Sciences.

"It's quite the serendipitous discovery," said Quasar Padiath, M.B.B.S., Ph.D., associate professor in the Pitt Graduate School of Public Health's Department of Human Genetics and one of the senior authors on the research. "Just like everyone else, I thought we knew how the cellular nuclear envelope was organized, but as we took a closer look while investigating a genetic condition, we found that there was far more to the story."

Every animal cell contains a nucleus, home to the majority of its genetic material. Lining the interior of the membrane encasing the nucleus is the nuclear lamina, a scaffold that gives the nucleus its spherical structure. Scientists had previously shown the lamina to be formed by a tangled meshwork of filaments, made up of proteins called lamin A and B.

Padiath teamed up with Yang Liu, Ph.D., associate professor in Pitt's departments of medicine and bioengineering, to take a closer look at the nuclear lamina because people with a fatal genetic condition he studies - autosomal dominant leukodystrophy with autonomic disease (ADLD) - have extra copies of the gene that codes for lamin B1, a subtype of lamin B. The scientists first looked at the lamina in normal cells using a super-resolution imaging technique called "stochastic optical reconstruction microscopy" (STORM).

To their surprise, the team discovered that there are actually two distinct meshworks - an outer, more loosely woven layer of lamin B and an inner, tighter layer of lamin A.

"It is truly remarkable that STORM is able to visualize such a microscopically small separation between lamin A and B1," said Liu, who also is a researcher at the UPMC Hillman Cancer Center. "That has never been seen with conventional light microscopy."

Padiath's team then built on an ongoing partnership with Kris Dahl, Ph.D., a Carnegie Mellon University professor of chemical engineering who studies the mechanics and architecture of nuclear membranes, to learn about how the lamin layers function. By imaging nuclei under varying degrees of pressure, the scientists discovered that when a cell is compressed, the outer, more loosely woven lamin B1 layer thins, allowing the lamin A layer to bulge out at the axes of the nucleus.

"For me, this process is similar to one of my knitting projects," said Dahl. "Based on the holes between the stitches and the thickness of the yarn, you can predict the stiffness of the material."

The scientists believe their observations indicate that the distinct lamin layers are part of a necessary cellular system: When functioning correctly, it allows nuclei to relieve pressure when compressed by biologic functions - such as moving within a very thin blood vessel or squeezing through a narrow opening - to avoid damage to the nucleus itself.

In the disease that Padiath studies - ADLD - patients typically live into their 40s and 50s before experiencing symptoms tied to fatal brain degradation. Because ADLD involves extra copies of the lamin B1 gene, Padiath's future work will explore how excessive lamin B could negatively impact brain cells at middle age.

"Now that we can look at the nuclear architecture in such exquisite detail, we can start asking, 'How does it change in ADLD and other lamina diseases, particularly with aging?'" Padiath said.
Additional authors on this paper are Bruce Nmezi, B.S., Jianquan Xu, Ph.D., Rao Fu, Ph.D., Guillermo Bey, Ph.D., Juliana Powell, B.S., Hongqiang Ma, Ph.D., Mara Sullivan, B.S., and Donna Stolz, Ph.D., all of Pitt; Travis Armiger, Ph.D., of Carnegie Mellon University; Yiping Tu, Stephen Young, M.D., and Natalie Chen, B.S., all of the University of California, Los Angeles.

This work was supported by National Institutes of Health grants R01NS095884, EB003392, R01EB016657, R01CA185363, 1S10RR019003-01 and 1S10RR025488-01; National Multiple Sclerosis Society grant 5045A1, and National Science Foundation grant CMMI-1634888.

About the University of Pittsburgh Schools of the Health Sciences

The University of Pittsburgh Schools of the Health Sciences include the schools of Medicine, Nursing, Dental Medicine, Pharmacy, Health and Rehabilitation Sciences and the Graduate School of Public Health. The schools serve as the academic partner to the UPMC (University of Pittsburgh Medical Center). Together, their combined mission is to train tomorrow's health care specialists and biomedical scientists, engage in groundbreaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care. Since 1998, Pitt and its affiliated university faculty have ranked among the top 10 educational institutions in grant support from the National Institutes of Health. For additional information about the Schools of the Health Sciences, please visit

University of Pittsburgh

Related Genetic Diseases Articles:

Screening for genetic diseases & chromosomal defects with a single biopsy improves pregnancy rates
Couples who are undergoing pre-implantation genetic diagnosis (PGD) in order to avoid transmission of inherited diseases, such as Duchenne muscular dystrophy or cystic fibrosis, should also have their embryos screened for abnormal numbers of chromosomes at the same time, according to research published in Human Reproduction journal.
New software tool could help doctors diagnose genetic diseases
An open-source software tool called Mendel,MD could help doctors analyze patients' genetic data in order to diagnose diseases caused by mutations.
Unveiling the bottlenecks to discovering the root causes of rare genetic diseases
A commentary paper including feedback from 40 scientists, says international cooperation is needed now more than ever; despite advances in technology and decades of research, the genetic mutations behind half of the 7,000 known rare genetic diseases in the world remain a mystery.
Unveiling how nucleosome repositioning occurs to shed light on genetic diseases
A research group led by a Waseda University professor became the first in the world to unveil the three-dimensional structure of an overlapping dinucleosome, a newly discovered chromatin structural unit.
Stem cell consortium tackles complex genetic diseases
Much of stem cell research over the past decade has focused on Mendelian disorders -- those caused by a single gene, such as cystic fibrosis, muscular dystrophy, and Huntington's disease.
Drosophila effectively models human genes responsible for genetic kidney diseases
The majority of genes associated with nephrotic syndrome (NS) in humans also play pivotal roles in Drosophila renal function, a conservation of function across species that validates transgenic flies as ideal pre-clinical models to improve understanding of human disease, a Children's National Health System research team reports in a recent issue of Human Molecular Genetics.
Stepping up the hunt for genetic diseases
The child's own genome thus consists of a maternal and a paternal genome.
Study of complex genetic region finds hidden role of NCF1 in multiple autoimmune diseases
Medical University of South Carolina investigators report pre-clinical research showing that a genetic variant encoded in neutrophil cystolic factor 1 (NCF1) is associated with increased risk for autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjögren's syndrome, in the January 2017 issue of Nature Genetics.
Large Finnish genetic study uncovers potential new treatments for inflammatory diseases
Researchers from the Research Centre of Applied and Preventive Cardiovascular Medicine at the University of Turku, Finland, have studied over ten million DNA variations and found new links between the human genome and inflammation tracers.
Genetic risk factors for autism, MS and other diseases differ between the sexes
A pair of studies by researchers at UC San Francisco suggest that genetic variants that have distinct effects on physical traits such as height, weight, body mass, and body shape in men versus women are also linked to men's and women's risk for a range of diseases -- including autism, multiple sclerosis, type 1 diabetes, and others.

Related Genetic Diseases Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".