{"id":9569,"date":"2018-10-24T10:55:46","date_gmt":"2018-10-24T14:55:46","guid":{"rendered":"https:\/\/biology.mit.edu\/?p=9569"},"modified":"2018-10-24T10:55:46","modified_gmt":"2018-10-24T14:55:46","slug":"only-in-your-head","status":"publish","type":"post","link":"https:\/\/biology.mit.edu\/only-in-your-head\/","title":{"rendered":"Only in Your Head"},"content":{"rendered":"
Cambridge, Mass. — Brain development is a delicately choreographed dance in which cell division and differentiation into mature cell types must be performed in the right balance for normal growth. In order to better understand factors affecting brain development, Whitehead Institute researchers investigated a genetic mutation that leads to a brain-specific developmental disorder in spite of the gene\u2019s prevalent expression in other cell types.<\/p>\n
Kinetochore null protein 1 (KNL1) acts throughout the body during cell division to help ensure the accurate segregation of chromosomes into each daughter cell. A mutation in the KNL1 gene caused by a single change in its DNA sequence leads to microcephaly, a condition in which the brain fails to properly develop, causing babies to be born with small heads, often accompanied by intellectual disabilities and other health problems. In an article published online October 9 in the journal\u00a0Cell Reports<\/em>, Whitehead Institute Founding Member\u00a0Rudolf Jaenisch<\/a>\u00a0and colleagues investigated how this KNL1 mutation can lead to microcephaly without affecting other cell types, providing important insights into the underlying basis of microcephaly and the role that KNL1 normally plays in brain development.<\/p>\n \u201cThe key question we were interested in was why, if the gene is ubiquitously expressed, is there a brain-specific phenotype,\u201d says Jaenisch, who is also a professor of biology at the Massachusetts Institute of Technology.<\/p>\n Jaenisch lab graduate student Attya Omer Javed, a co-first author on the paper along with past lab members Yun Li and Julien Muffat, used CRISPR-Cas9 to recreate the mutation\u2014a point mutation, or one-letter change in the DNA sequence of the KNL1 gene\u2014in several different cell types derived from human stem cells in the lab. Of the three cell types tested, they found that only the neural progenitor cells, early stage cells that become brain cells, appeared to be affected.<\/p>\n As the brain develops, each neural progenitor can either keep dividing to increase the overall number of cells in the brain, or it can mature into a differentiated brain cell, at which point it is no longer able to divide. For a healthy brain to develop, there needs to be a careful balance between these two processes of proliferation and differentiation. If the progenitors take too long to differentiate, the developing brain won\u2019t have the specific cells it needs to assemble. But if all of the cells differentiate too quickly, before they can divide, there will be a shortage of cells and the brain will be too small.<\/p>\n \u201cNeural progenitors are going through many cell cycles, dividing quickly during brain development. Even a small defect could accumulate to have a huge impact,\u201d Omer Javed says.<\/p>\n The researchers discovered that neural progenitors with the KNL1 mutation differentiated prematurely at the cost of proliferation, resulting in the small brain size that characterizes microcephaly. The brain cells with the mutation also were at a greater risk of cell death, disruption of the cell cycle, ending up with the wrong number of chromosomes, and malfunctions during attempted cell division.<\/p>\n