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"Nerve pruning" - Its a thing

While investigating the molecular mechanics behind human motor disabilities, scientists gave mice more flexible wrists...


Motor disabilities may be the result of developing nerves being blocked by chemical "pruning" of these new brain-to-limb connections. In modified lab mice, this "pruning" results in increased manual dexterity which allows those mice to grab and eat food much faster than regular wild-type mice.

The study is published July 28, 2017 in the journal Science.

Scientists at Cincinnati Children's Hospital Medical Center who led the study stress they weren't trying to create a genetically superior mouse. They were just testing how the nervous system forms connections during early development using a mouse model.
Their goal was to understand how sophisticated nerve connections begin forming in wild baby mice, but disappear as the animals mature. Understanding this process might one day help human patients.

The study points out how a class of proteins called semaphorins, control the formation of long thread-like nerves called axons and all the motor neuron connections made in the mammalian corticospinal (CS) system. A semaphorin's job is to prevent axons from forming in inappropriate regions of the nervous system.
In particular, the scientists identified how a protein called PlexA1, is a major receptor type molecule attracting semaphorins.

As mice spend most of their time on four paws, signaling between semaphore proteins called Sema6, and PlexA1 begins early in development. This interaction eliminates critical synaptic links between nerve cells, stopping the formation of fine CS neural connections and the resulting increased flexibility in ankles and wrists.

According to Yutaka Yoshida, lead study investigator in the Division of Developmental Biology at Cincinnati Children's: "We may have found a pivotal point in the evolution of the mammalian corticospinal (CS) system that leads to greater fine motor control in higher primates and people.

"Although we still need to explore this, it's possible that some patients with motor disabilities have upregulated expression [an increased amount] of PlexA1 signaling that diminishes their cortico-motor-neuron connections and fine motor skills. Inhibiting PlexA1 signaling in early childhood might be a way to restore these fine motor skills."


After learning how PlexA1 protein eliminates fine motor neuron connections in maturing mice, researchers then bred mice without the protein. As these PlexA1 mutant mice matured into adulthood, their feeding tests were significantly better and faster than normal mice when grabbing and eating food. However, mutant PlexA1 mice were less skilled in walking, not performing any better than normal mice. Perhaps wobbly ankles were to blame.

To better understand these differences between mice and humans, the authors compared genetic and molecular regulation of CS neural connections in both the mouse and human motor cortex — the region that controls voluntary movements and other critical tasks. Human tests of the motor cortex were performed on donated human brain tissue. From these comparisons, they determined how variation in PlexA1 expression is caused by cis-regulatory elements. These are regions of non-coding DNA that help regulate nearby genes. A transcription factor or gene that tells other genes what do to, called FEZF2 interacts with cis-regulatory elements and directs the formation of neural transmitter connections in CS neurons.
FEZF2-controlled cis-regulatory elements are found in human brain tissues and in other higher primates such as chimpanzees — but not in mice. These regulatory elements suppress PlexA1 in developing human CS connections, protecting sophisticated motor neuron connections from becomming disrupted as infants mature over years into adults.

Yoshida and colleagues emphasize additional research is needed before determining how these findings might apply to clinical practice. But the data from the study provides a number of clues in determining whether varying motor disabilities are the result of mutations in the Sema6 -PlexA1 molecular signaling pathway.

Structured Abstract

Introduction
In human cells, 2 m of DNA are compacted in the nucleus through assembly with histones and other proteins into chromatin structures, megabase three-dimensional (3D) domains, and chromosomes that determine the activity and inheritance of our genomes. The long-standing textbook model is that primary 11-nm DNA–core nucleosome polymers assemble into 30-nm fibers that further fold into 120-nm chromonema, 300- to 700-nm chromatids, and, ultimately, mitotic chromosomes. Further extrapolating from this model, silent heterochromatin is generally depicted as 30- and 120-nm fibers. The hierarchical folding model is based on the in vitro structures formed by purified DNA and nucleosomes and on chromatin fibers observed in permeabilized cells from which other components had been extracted. Unfortunately, there has been no method that enables DNA and chromatin ultrastructure to be visualized and reconstructed unambiguously through large 3D volumes of intact cells. Thus, a remaining question is, what are the local and global 3D chromatin structures in the nucleus that determine the compaction and function of the human genome in interphase cells and mitotic chromosomes?

Rationale
To visualize and reconstruct chromatin ultrastructure and 3D organization across multiple scales in the nucleus, we developed ChromEMT, which combines electron microscopy tomography (EMT) with a labeling method (ChromEM) that selectivity enhances the contrast of DNA. This technique exploits a fluorescent dye that binds to DNA, and upon excitation, catalyzes the deposition of diaminobenzidine polymers on the surface, enabling chromatin to be visualized with OsO4 in EM. Advances in multitilt EMT allow us to reveal the chromatin ultrastructure and 3D packing of DNA in both human interphase cells and mitotic chromosomes.

Results
ChromEMT enables the ultrastructure of individual chromatin chains, heterochromatin domains, and mitotic chromosomes to be resolved in serial slices and their 3D organization to be visualized as a continuum through large nuclear volumes in situ. ChromEMT stains and detects 30-nm fibers in nuclei purified from hypotonically lysed chicken erythrocytes and treated with MgCl2. However, we do not observe higher-order fibers in human interphase and mitotic cells in situ. Instead, we show that DNA and nucleosomes assemble into disordered chains that have diameters between 5 and 24 nm, with different particle arrangements, densities, and structural conformations. Chromatin has a more extended curvilinear structure in interphase nuclei and collapses into compact loops and interacting arrays in mitotic chromosome scaffolds. To analyze chromatin packing, we create 3D grid maps of chromatin volume concentrations (CVCs) in situ. We find that interphase nuclei have subvolumes with CVCs ranging from 12 to 52% and distinct spatial distribution patterns, whereas mitotic chromosome subvolumes have CVCs >40%.

Conclusion
We conclude that chromatin is a flexible and disordered 5- to 24-nm-diameter granular chain that is packed together at different concentration densities in interphase nuclei and mitotic chromosomes. The overall primary structure of chromatin polymers does not change in mitotic chromosomes, which helps to explain the rapid dynamics of chromatin condensation and how epigenetic interactions and structures can be inherited through cell division. In contrast to rigid fibers that have longer fixed persistence lengths, disordered 5- to 24-nm-diameter chromatin chains are flexible and can bend at various lengths to achieve different levels of compaction and high packing densities. The diversity of chromatin structures is exciting and provides a structural basis for how different combinations of DNA sequences, interactions, linker lengths, histone variants, and modifications can be integrated to fine-tune the function of genomic DNA in the nucleus to specify cell fate. Our data also suggest that the assembly of 3D domains in the nucleus with different chromatin concentrations, rather than higher-order folding, determines the global accessibility and activity of DNA.

All authors: Horng D. Ou, Sébastien Phan, Thomas J. Deerinck, Andrea Thor, Mark H. Ellisman, Clodagh C. O’Shea


Funding support for the study came from: the National Institutes of Health (R01 NS099068, R21HG008186 and R01NS079569); the Lupus Research Alliance "Novel Approaches" award; a Cincinnati Children's Center for Pediatric Genomics pilot study award, and the National Institute of Neurological Disorders and Stroke (NS093002).

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Aug 24, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




Eight days after researchers injected an altered rabies virus into a mouse's forelimbs to trace nerve growth, a cross section of that animal's brain showed neural connections were missing (right side)
as a result of eliminating the protein PlexA1. Scientists studying motor disabilities found stopping
nerve pruning by PlexA1 - a normal process in developing mice - allowed nerve connections
to continue to grow in adult mice - but negatively affected the adults' ability to walk and run.
Image credit: Cincinnati Children's Hospital



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