Nerve Pruning in Mice Sheds Light on Human Fine Motor Control

Researchers investigating why some people suffer from motor disabilities have found an interesting developmental clue from studying how mice prune their own nerve connections as they grow.

Young mouse brains actually start out with more brain-to-limb nerve connections than they ultimately keep. At birth, their forepaws possess motor neuron connections that closely resemble a dexterous human or primate hand.

However, since mice spend so much of their lives on all fours, their front paws also need to serve as feet. So within two weeks after birth, a class of proteins called semaphorins kick in to make some of those neuron connections driving dexterity disappear.

Now, a multinational research team led by Zirong Gu, PhD, and Yutaka Yoshida, PhD, has detailed how this process works, which raises hopes that someday this learning could be used to help people with conditions affecting motor control.

The team identified a signaling pathway between the PlexA1 and Sema6 proteins that attracts semaphorins to prevent inappropriate axon formation. Surprisingly, when this pathway was suppressed, mice developed sharply enhanced manual dexterity, retrieving and grasping food much faster than wild-type mice.

“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,” Yoshida says.

Developing a dexterous mouse

After learning the PlexA1 protein eliminates sophisticated motor neuron connections in maturing mice, the researchers bred mice that do not express the PlexA1 gene. In feeding tests involving strands of pasta and food pellets, mutant PlexA1 mice were significantly more skilled and faster than normal mice at grabbing food. They also outperformed wild-type mice in a sticky tape removal test.

However, the mutant mice did not show any higher grasping strength than wild-type mice, nor did they show any elevated skills in walking tests.

In comparing mouse and human tissues, the team determined that the transcription factor FEZF2 interacts with cis-regulatory elements to connect neural transmitters in CS neurons. In humans, these regulatory elements also suppress PlexA1, thus preventing sophisticated motor neuron connections from being disrupted as infants mature. However, these cis-regulatory elements are not found in mice.

Although it might seem that mice would benefit from enhanced CM connections, the authors explain that they may be eliminated because increased manual dexterity offers no advantages to quadrupedal animals, and may even become a burden. For example, maintenance of CM connections in mice may disrupt the development and function of other spinal motor circuits, such as those for forelimb locomotion rather than manipulation.

Can unwanted nerve pruning be prevented?

“Although we still need to explore this, it is possible that some patients with motor disabilities have upregulated expression of PlexA1 or activated PlexA1 signaling that diminishes corticomotor neuron connections and fine motor skills,” Yoshida says. “Inhibition of PlexA1 signaling during childhood might be a way to restore these skills.”

Looking forward, Yoshida and colleagues plan to explore whether people with various motor disabilities have mutations in the Sema6 -PlexA1 signaling pathway.

This project involved 21 collaborators in eight research centers in the U.S., Japan and China, including eight members of the divisions of Biomedical Informatics and Developmental Biology at Cincinnati Children’s and the Center for Autoimmune Genomics and Etiology.

Citation

Gu Z, Kalambogias J, Yoshioka S, Han W, Li Z, Kawasawa YI, Pochareddy S, Li Z, Liu F, Xu X, Wijeratne HRS, Ueno M, Blatz E, Salomone J, Kumanogoh A, Rasin MR, Gebelein B, Weirauch MT, Sestan N, Martin JH, Yoshida Y. Control of species-dependent cortico-motoneuronal connections underlying manual dexterity. Science. 2017 Jul 28;357(6349):400-404.