Life finds a way: origami at subcellular scales.

Alphy John and Kavya Vinayan Pushpalatha

Every individual life on Earth assumes a distinctive shape to fulfill its function. In the realm of multicellular organisms, the culmination of form is achieved through the intricate process of cellular origami. Groups of cells fold, twist, turn, migrate, exchange neighbors, thicken, thin, grow, and shrink, collectively contributing to the emergence of the organism's final structure. Previous extensive research, combining quantitative bioimaging and computational modeling, has unveiled common principles of morphogenesis that play a pivotal role in sculpting these organisms [1,2].

The mechanisms driving tissue-scale origami are well-studied during development, emerging as a universal morphogenetic program driving processes such as tubulogenesis and pit/gland formation. Interestingly, tissue-scale origami is tightly regulated by a genetic program, guided by gene expression patterns and morphogen gradients. This implies that time plays an important factor, with tissue-scale origami occurring on the order of minutes to hours to days.

It is intriguing how time-consuming processes like transcription or translation contribute to biological processes happening at millisecond to second timescales. For example, unicellular protists extend protrusions within a fraction of seconds to catch their prey, or membrane invaginations occur during Drosophila embryonic cellularization within moments. How can life sustain these fast processes? One answer to this problem is sub-cellular scale origami!

One of the first examples of subcellular origami was identified during the cellularization of the Drosophila embryo. A fertilized Drosophila zygotic nucleus undergoes the first fourteen divisions without forming cell membranes, making it a syncytium. During these division cycles, the nuclei slowly migrate to the boundaries from the center. By the end of the fourteenth cell cycle, they reach the boundary, and each nucleus is then wrapped around by a distinct cell membrane along its lateral and basal surfaces, creating distinct cells. This process, called cellularization, generates cells that are 50 μm long. Research from the Sokac lab has shown that the plasma membrane is stored as folded microvilli on the apical surface of individual nuclei. These microvilli unfold and fuel the membrane ingression during cellularization [3].

A recent and compelling example of subcellular origami has been discovered by the Prakash lab in the unicellular swan-necked predator Lacrymaria olor, which is available as a preprint on bioRxiv [4]. L. olor is a 40 μm long unicellular ciliate. During hunting, it attaches to a sessile substrate and extends its swan-neck or protrusion to catch prey. The neck of L. olor is hyperextensible; it can grow up to 1500 μm within 30 seconds and retract back in the same time frame. L. olor extends its protrusion reaching up to 30 times its body length and retracts at an extension and contraction rate of approximately 1000 μm/s. This process is highly reversible and repeatable, with L. olor unfailingly repeating it around 20,000 times during its lifetime.

Shape changes during hunting cycle of Lacrymaria olor. Image taken from: Flaum and Prakash 2023.

The question arises: Why would evolution favor such a mechanism that generates high stress and strain over other mechanisms? In previous elegant work from the same team, using a fast imaging and remapping approach, they demonstrated that this mode allows L. olor to sample a wider area of its hunting ground [5,6]. However, this highly repeatable hyperextension paradigm introduces a challenge for L. olor: How can a cell produce such a large amount of membrane and cortical cytoskeleton to support this hyperextension without undergoing rupture?

In their preprint, Manu and his team uncover a mechanism of curved-crease origami at play to support L. olor hyperextension. In this study, they have discovered distinct organizations of cell cytoskeleton and membrane. The microtubules form a continuous helix from the base of the body to the extension, with a smaller pitch at the base of the body and a longer pitch in the extension. Using experimental and modeling approaches, they have shown that the extension and retraction of L. olor's swan-neck are mediated by the regulated spooling and unspooling of microtubule filaments [4].   

Schematic of membrane unfolding dynamics during L.olor extension and contraction cycle. Image taken from Flaum and Prakash 2023.

Graphical represenation of the membrane unfolding during L.olor extention and contraction cycle.

A fundamental limitation that has long intrigued developmental biologists is how much a cell can modulate its shape without damaging itself. The answer is clear: Life always finds its way.

Why we chose this study: Subcellular origami is a mix of biology and folding that can help us find new ways to make things stretchy, which can be super important for medical tools and making strong materials.

References     

1            Gilmour, D., Rembold, M. & Leptin, M. From morphogen to morphogenesis and back. Nature 541, 311-320 (2017). https://doi.org:10.1038/nature21348

2            Perez-Vale, K. Z. & Peifer, M. Orchestrating morphogenesis: building the body plan by cell shape changes and movements. Development 147 (2020). https://doi.org:10.1242/dev.191049

3            Figard, L., Xu, H., Garcia, H. G., Golding, I. & Sokac, A. M. The plasma membrane flattens out to fuel cell-surface growth during Drosophila cellularization. Dev Cell 27, 648-655 (2013). https://doi.org:10.1016/j.devcel.2013.11.006

4            Flaum, E. & Prakash, M. Curved crease origami and topological singularities at a cellular scale enable hyper-extensibility of Lacrymaria olor. bioRxiv (2023). https://doi.org:10.1101/2023.08.04.551915

5            Coyle, S. M., Flaum, E. M., Li, H., Krishnamurthy, D. & Prakash, M. Coupled Active Systems Encode an Emergent Hunting Behavior in the Unicellular Predator Lacrymaria olor. Curr Biol 29, 3838-3850 e3833 (2019). https://doi.org:10.1016/j.cub.2019.09.034

6            Krishnamurthy, D. & Prakash, M. Emergent programmable behavior and chaos in dynamically driven active filaments. Proc Natl Acad Sci U S A 120, e2304981120 (2023). https://doi.org:10.1073/pnas.2304981120