Early Stem Cell Mutation Linked to Rett Syndrome

A communication release by the Burnham Institute for Medical Research claims that a study by Burnham scientists shows that neural stem cell development may be linked to Rett Syndrome. The study published today in the early online edition of the Proceedings of the National Academy of Sciences, reports that mice lacking the myocyte enhancer factor 2C (MEF2C) protein in neural stem cells had smaller brains, fewer nerve cells and showed behaviors similar to those seen in humans with Rett Syndrome. The communique claims that the study represents the first direct link between a developmental disorder of neural stem cells and the subsequent onset of autism.

The research team was led by Stuart A. Lipton, M.D., Ph.D., a clinical neurologist and Professor and Director of the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at Burnham who expressed optimism that the results of the study could lead to correction of the mutation in mice and ultimately in humans:

"These results give us a good hint of how to look at Rett Syndrome and potentially other forms of autism in humans," said Dr. Lipton. "Having identified a mutation that causes this defect, we can track what happens. Perhaps we can correct it in a mouse, and if so, eventually correct it in humans."

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Autism May Result from Wrong Amount of MeCP2 Protein, Wrong Number of Synapses

“MeCP2 has an important role in fine-tuning the amount of synaptic responses, having just the right amount of MeCP2 and the right number of synapses drives healthy brain development"

- Hsiao-Tuan Chao, M.D./Ph.D. graduate student, Baylor College of Medicine

A study published in Neuron reports evidence that problems in synapse formation early in post natal development give rise to mental retardation, Rett syndrome, autism and other developmental disorders. The protein MeCP2 (methyl-CpG binding protein 2) is critical in determining the number of synapses. And the correct number of synapses is necessary for healthy brain development. A mutation of the MeCP2 gene results in too little of the protein which further results in girls developing Rett syndrome. Boys with too much MeCP2 have spasticity and mental retardation with autism-like behavior.

In MeCP2 Controls Excitatory Synaptic Strength by Regulating Glutamatergic Synapse researchers Hsiao-Tuan Chao, Huda Y. Zoghbi, and Christian Rosenmund of the Baylor College of Medicine report conclusions of their study of two groups of mice, one group of mice with too little MeCP2, and another group with too much of the protein, to figure out what is the right number of synapses and how the number is determined. The found that too little of the MeCP2 protein meant that not enough synapses formed. Too much MeCP2 meant too many synapses formed.

As reported on the Baylor College of Medicine web site:

“The beauty of this result is that this critical process in the development of synaptic connectivity in the brain is tightly regulated by the amount of MeCP2,” said Rosenmund. “It is one of the strongest pieces of evidence that mental retardation and autism-like diseases originate with problems in synapse formation.”

Chao said, “It suggests that the pathways in which MeCP2 is involved and the proteins it regulates are probably critical for how the brain can determine how many synapses to make as it’s developing.”

“This determination of how many synapses to make happens early in life,” said Zoghbi. “If it’s not right, then the brain undergoes secondary changes to try to compensate. This is a big important observation and opens up ways to think about adult diseases that involve loss of synaptic function. It is also interesting that patients who lack this protein or have too much have features of autism. More and more, data point to the possibility that autism is a disorder of abnormal function of the synapse.”

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