Monday, July 28, 2014

Canadian Team Discovers Master Gene for Motor Development

This illustration shows the cerebellum's location in the human brain. Illustration: Alan Hoffring, National Cancer Institute, public domain image.

A Canadian research team announced in 2014 they had discovered a master control gene - Snf2h - critical for development of the cerebellum. The cerebellum (Latin for or little brain) at the base of the skull coordinates muscle contractions for smooth movement, muscle tone at rest, and helping maintain balance.

About half your entire brain's neurons are found in the cerebellum; it's a tightly-packed twin-hemisphere hindbrain region, with much denser surface folds than the outer surface of the main brain - the cerebral cortex (Latin for brain bark). Its hundreds of millions of neurons primarily relay information between muscles of the body and motor control regions of the cerebral cortex. It acts as a comparator, using mismatches between intentions and actual movement as an error-correction guide to produce fine, complex movements. 

Most information about the cerebellum's function is derived from examining humans and animals with damage to the region. Subjects with cerebellar damage  suffer from major motor control problems, ipsilateral (on the opposite side of the body) to the damaged cerebellar lobe. While they can still produce movement, it is uncoordinated, mistimed, or erratic. Coupled with fMRI scans, this indicates the region fine tunes and coordinates, rather than initiates or selects movement. Recent findings also indicate the cerebellum is not solely motor-related, as it also activates during functions related to mental imagery, attention, motor learning and language.

The cerebellum develops in response to external stimuli and practice, switching specific genes or gene groups on and off, and strengthening circuits to consolidate and perfect complex tasks. Here Snf2h coordinates this complex, ongoing process.

Master genes like Snf2h are epigenetic (above the gene) regulators, which can adapt according to environmental cues such as diet or stress, then adjust which genes are switched on or off.

Dr. David Picketts of the Ottawa Hospital Research Institute and University of Ottawa led the team which discovered Snf2h along the fourth chromosome (DNA strand) in the nuclei of neural stem cells. According to Dr. Picketts, master neural epigenetic regulators like Snf2h affect memory, behavior and learning. It is highly conserved (found unchanged) in animals including mice, indicating it existed at least 75 million years ago, when the common ancestor to mice and humans first evolved. 

Silencing Snf2h in developing mice embryos results in cerebella one-third the normal size, with consequent errors in walking, balance and coordinated movement. Such impairment, cerebellar ataxia, is common among sufferers of neurodegenerative diseases.

When cerebellar stem cells divide, en route to specializing as specific neurons, Snf2h determines which genes will be activated and which genes will be curled up inaccessibly along the DNA strands. Without its guidance, some vital genes remain inactivated, while others which hinder development remain switched on. The result is sparser neurons, which don't respond and adapt to external signals efficiently. Gene expression in the cerebellum becomes progressively more disorganized, leading to cerebellar ataxia and premature death for the afflicted.

Source: Researchers find gene critical for development of brain motor centre, News Release, June 20, 2014, Paddy Moore, Ottawa Hospital Research Institute

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