Pushing the Nuclear Envelope

Newswise — Hollyood's silliest cell biology sci-fi flick was arguably the 1966 epic Fantastic Voyage. We can now answer a question that has surely dogged fans ever since Dr. Duval's crack surgical team (including "beautiful assistant" Raquel Welch) was shrunk down to "molecule size" and injected into the bloodstream of a critically ill patient: what would it feel like to bump into a cell's nuclear envelope?

Kris Dahl, working with Professor Dennis Discher in the Chemical and Biomolecular Engineering Department at Penn, directly measured the physical properties of the nuclear envelope. Their data suggests that the nuclear envelope acts like a "molecular shock absorber," protecting the precious genetic material inside from the hard knocks of cellular life.

Forty years ago, few cell biologists, let alone the producers of Fantastic Voyage, knew anything about the nuclear envelope. Times have changed. Once considered little more than a passive container for chromosomes, the cell nucleus is now recognized as dynamic organelle—the "Mothership of the Human Genome" as one researcher calls it— with active roles in organizing chromatin, facilitating gene expression and DNA replication, and resisting disease. The nuclear envelope is 'double-hulled,' composed of two concentric membranes separated by a functional aqueous space, and embedded with pore complexes that regulate movement across the envelope. However the most important feature, in terms of mechanical properties, is a network of filaments formed by the polymerization of lamin proteins. This polymer network, the 'lamina,' is closely associated with the inner membrane. Collectively, these components of the nuclear envelope serve as the mothership's tough outer skin.

Just how tough is the nuclear envelope? To find out, Dahl and colleagues first isolated nuclei from oocytes of the African clawed toad, Xenopus laevis. Xenopus oocyte ('XO') nuclei are used widely to study nuclear envelope structure. They then measured the mechanical properties of these nuclear envelopes, either attached to or detached from the chromatin inside, using a full range of biophysical techniques including fluorescence labeling, controlled swelling and micropipette aspiration.

They found that the XO nuclear envelope had two major properties: it resisted forces applied from the outside, yet was amazingly elastic when subjected to pressure from inside the nucleus. Micropipette aspiration of XO envelopes yielded a "network elastic modulus" averaging 25 mN/m and exhibited what bioengineers call "the ability to sustain large dilational strains," i.e., it stretches beautifully, "like a thin sheet of latex rubber," according to Discher.

After applying square-net simulations and comparing polymer network models to their XO data, Dahl and colleagues concluded that the physical properties of the nuclear envelope were largely determined by the lamina network. They are especially intrigued by the lamina's ability to resist external forces. The XO lamina, it turns out, is 'compressed' in its native state (somewhat like the steel cables used to create 'pre-stressed' concrete beams in bridges and overpasses), and behaves as an interconnected network of short, stiff rods. This discovery was made possible by the XO nuclei, which have a 'typical' DNA content but are significantly larger than somatic (non-embryonic) nuclei, making it relatively easy to study the properties of the nuclear envelope alone.

In contrast, they found that the physical properties of mammalian somatic nuclei are dictated by interconnections between the lamina and chromosomes, which fill somatic nuclei. When chromatin organization is disrupted, somatic nuclei become less rigid and act like XO nuclei: their lamina network reveals the flexibly compressed state that allows for membrane deformation and the stiffness that protects the contents of the nucleus. "These results show substantial expansion and shear flexibility of the lamina," says Dahl. "The resulting model suggests a unique architecture of the lamina which allows it to act as a 'molecular shock absorber'."

The nuclear envelope lamina network has elasticity and a compressibility limit suggestive of a "molecular shock absorber," K. N. Dahl,1 K. L. Wilson,2 D. E. Discher,1 ; 1 Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, 2 Department of Cell Biology, Johns Hopkins University, Baltimore, MD.

At the meeting: Session 272, Minisymposium 11: The Nuclear Envelope: Structure & Transport Mechanisms, Ballroom C. Author presents: Monday, Dec. 6, 3:40 — 5:45 PM.