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Developmental biology - Evolutionary Genetics

Intestinal Tether System Pulls Cells Into Place

A new study shows how developing intestine grows in a surprising sequence of death-defying, high-wire circus moves...

More than 40 percent of our small intestine develops before we are even born. In adulthood, this organ stretches more than three times the length of our entire body. But problems with the intestinal process in utero can result in a rare but deadly condition known as congenital short bowel syndrome, which can lead to dehydration, malnutrition and weight loss during infancy.

A new study examining how the developing intestine grows in mice found a surprising sequence of cellular events akin to a death-defying, high-wire circus performance, before intestines can reach their proper length. A lack of coordination between cell movements could kill the cell.

Sha Wang PhD, Department of Cell and Developmental Biology at the University of Michigan Medical School, USA and her colleagues were able to witness this intricate choreography in real-time in mouse gut cells. The developing small intestine, or midgut, starts out as a smooth tube undergoing rapid growth. Under a microscope, the thin layer of epithelial cells lining that intestinal tube, appear to be stacked in layers. Previously, scientists believed the intestinal tube grew longer as cells moved between these "stacks" of cells to form one continuous layer.

"When you think about it, if the midgut lengthened through the convergence of cells, it would sacrifice girth (it would become thinner). But instead - the tube gets wider," says Wang. Instead, she and U-M cell biologist Deb Gumucio PhD and their team were able to show that elongation is likely powered by rapid cell division.

Their results are published in Developmental Cell.

A high-stakes process

The team found that during the first phase of midgut development, cells are very tall and thin. The nucleus of each cell moving constantly within the epithelial cell layer, from the base (or basal) surface to the top (or apical) surface. Much like a trapeze artist climbing up to their starting platform.
"Movement is tied to cell division. Once the nucleus is at the top of the cell, the cell will undergo mitosis and split into two new cells."

Sha Wang PhD, Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

What happens next is critical. These two new daughter nuclei must make it back to the basal layer in order to re-enter another cell cycle. For one daughter cell, this step is simple: its nucleus simply follows a long, thin tether called a basal process back down to the basal layer. The other cell has a tougher job. It must extend an arm-like protrusion called a filopodium in the right direction before its own nucleus can follow that filopodium pathway back down to the basal layer.

midgut formation

Divide and prosper

Upon closer inspection of the basal process, Wang noticed that this thin tether would often divide itself into two strands - one longer and tethered to the base and a short strand that would retract and disappear. She suspects the reabsorbed and shorter filament may play a role in dividing the cytoplasm, which makes up most of the volume of each new daughter cell.
Wang: "The most interesting part is that cells keep one basal process to go to one daughter cell. But, the other cell also needs to find a connection back to the basal layer. Even in cases where both basal processes are kept, only one daughter cell keeps both of them."

She hypothesizes this is done on purpose to give one cell more flexibility in where it lands - but, creates greater risk. Telling up from down for the non-tethered cell, like a non-tethered acrobat, is a matter of life and death.

How cells find their way

There is something serving as a directional cue to help newly formed cells know which way to extend their filopodium. Researchers identified a likely candidate in a protein known as WNT5A, already known to help nerve cells grow similar projections called axons. WNT5A sends out a signal through the developing tissue, and new untethered cells will extend toward that signal finding their way back to the basal layer. When WNT5A is removed, newly forming cells are unable to find the direction to move toward - and die.
"According to our model, the death of just 10 percent of intestinal cells in the midgut can lead to a shortened intestinal length."

Sha Wang PhD.

• The early elongating midgut epithelium exhibits interkinetic nuclear migration
• Mitotic cells retain a thin basal process (BP), which is inherited by one daughter
• G1 nuclei return basally via a BP “conduit” or via “pathfinding” filopodia
• Mesenchymal WNT5A guides filopodial pathfinding, failure of which causes apoptosis.

The early midgut undergoes intensive elongation, but the underlying cellular and molecular mechanisms are unknown. The early midgut epithelium is pseudostratified, and its nuclei travel between apical and basal surfaces in concert with cell cycle. Using 3D confocal imaging and 2D live imaging, we profiled behaviors of individual dividing cells. As nuclei migrate apically for mitosis, cells maintain a basal process (BP), which splits but is inherited by only one daughter. After mitosis, some daughters directly use the inherited BP as a “conduit” to transport the nucleus basally, while >50% of daughters generate a new basal filopodium and use it as a path to return the nucleus. Post-mitotic filopodial “pathfinding” is guided by mesenchymal WNT5A. Without WNT5A, some cells fail to tether basally and undergo apoptosis, leading to a shortened midgut. Thus, these studies reveal previously unrecognized strategies for efficient post-mitotic nuclear trafficking, which is critical for early midgut elongation.

Authors: Sha Wang, Cristina Cebrian, Santiago Schnell, Deborah L. Gumucio.

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Jul 20, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

A midgut cell nucleus travels up from the basal layer [bottom of image] to the apical layer [top of image] to divide. A long protrusion tethers the nucleus to the basal layer, continually growing thinner and finally splitting in two. After the cell divides, one daughter cell nucleus uses this tether to be quickly guided back down to the basal cell layer. The other daughter cell must extend a new and thin filipodium to more slowly make the same trip. Image: Sha Wang, PhD.

Phospholid by Wikipedia