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Non-Zika microcephaly helps explain brain growth

Protein that helps new born brain cells divide, also plays a key role in brain expansion. Long before Zika virus became a household word, microcephaly as a birth defect puzzled scientists and doctors.

Now, new discoveries may help explain what happens in developing brains of babies causing them to be born with small brains and heads (microcephaly). The findings may also help scientists frantically trying to figure out why Zika causes the same problems in babies born to mothers bitten by a mosquito.

In two new papers in the American Journal of Human Genetics, researchers report a key protein found to be involved in generating new cells required to build a normal size brain. Neither study involved Zika-related microcephaly, but - they may provide clues that other scientists can use to investigate how Zika virus disrupts brain development.

Stephanie Bielas PhD, assistant professor of human genetics at the University of Michigan Medical School, helped lead the research. Bielas says the findings also help define what is required for brains to develop normally: "There is so much we don't understand about human brain development that we're just starting to uncover. This shows the devastating impact of interrupting cell biology critical for this process."

Both new papers focus on the role of the protein citron kinase (CIT as the protein is called for short) is important to the process of mitosis — when one cell divides to make two "daughter" cells. Mitosis is the foundation of all normal growth and development. CIT helps in the final stages of cell division, called cytokinesis, which then separates the two "daughter" cells. This is when the two new cells, each with their own copy of the the original "parent" DNA, severs the connections between them.

Years ago, research saw problems in the gene containing instructions for an animal form of CIT as microcephaly related. But, that link wasn't proven to exist in humans.

Today, research reveals CIT is just as critical in humans as in animals to building a normal sized brain.

To make this discovery, researchers studied families from Egypt, France and Turkey with one or more microcephalic babies. Some babies died soon after birth, others developed intellectual disabilities resulting from a too-small brain.

Studying these babies' genes and brain tissue, gave clues to the importance of CIT – and the problems that come when the CIT gene is mutated. Where normal brain cells have only one nucleus containing the DNA and other structures – in microcephalic brain tissue, many cells had multiple nuclei. This suggests something was preventing new cells from completely dividing into individual daughter cells.

With the parents' permission, a few stem cells were gathered from surviving childrens' skin cells and transformed into induced pluripotent stem cells (iPSCs). This process essentially turns back the clock on cells, making them pluri-potent or able to develop into nearly any type of cell.

Researchers then grew the iPSCs in culture dishes, coaxing them to develop into neural progenitor cells – cells that in a developing embryo grow and divide rapidly to become the future brain.

"There's a lot of evidence now that in microcephaly, there aren't sufficient numbers of neural progenitor cells to build a normal-size brain," says Bielas. "Since the cells that form the structures of the brain, develop from this pool of actively dividing cells, this aspect of human brain development is a key issue to study."

Bielas points out that studying rare spontaneous cases of microcephaly — such as those in the families that took part in the study — offers an opportunity to identify genes important to brain development, in order to understand the impact of deleterious small genetic mutations.

"Often in genetics, we identify seemingly obscure genes as the genetic basis of disorders; we don't know what they do or where and when they are active.

"But in the case of citron kinase, we knew what a mutation in the gene did in animal models.

"The newly published findings confirm that CIT mutations are not only linked to severe microcephaly in humans, but are also associated with a smooth, unfolded brain surface - known as lissencephaly. That association isn't usually seen in brain disorders linked primarily to defects in neural progenitor cell mitosis."

Stephanie L. Bielas PhD, Howard Hughes Medical Institute, Rady Children’s Institute of Genomic Medicine, University of California, San Diego, CA; Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY; Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, MI, all institutions within the USA.

Bielas and her colleagues are now growing brain "organoids" — or tiny balls of brain cells grown from iPSCs using edited genes — in order to see how brain tissue spontaneously develops. The hope is they will see the origin of microcephaly by watching organoids develop into human brain tissue. Perhaps they may see more clearly what might not be detected in animal models.

Some Zika researchers are also using this promising model system to study Zika's affect on ancestors to human neural cells. Bielas continues to seek more families with non-Zika microcephaly, to collect DNA samples that may yield more clues about microcephaly. "We need to know how microcephaly genes are contributing to such a profound human disorder," adds Bielas. "It's a puzzle we need to figure out."

Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly
Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

Mutations in Citron Kinase Cause Recessive Microlissencephaly with Multinucleated Neurons
Primary microcephaly is a neurodevelopmental disorder that is caused by a reduction in brain size as a result of defects in the proliferation of neural progenitor cells during development. Mutations in genes encoding proteins that localize to the mitotic spindle and centrosomes have been implicated in the pathogenicity of primary microcephaly. In contrast, the contractile ring and midbody required for cytokinesis, the final stage of mitosis, have not previously been implicated by human genetics in the molecular mechanisms of this phenotype. Citron kinase (CIT) is a multi-domain protein that localizes to the cleavage furrow and midbody of mitotic cells, where it is required for the completion of cytokinesis. Rodent models of Cit deficiency highlighted the role of this gene in neurogenesis and microcephaly over a decade ago. Here, we identify recessively inherited pathogenic variants in CIT as the genetic basis of severe microcephaly and neonatal death. We present postmortem data showing that CIT is critical to building a normally sized human brain. Consistent with cytokinesis defects attributed to CIT, multinucleated neurons were observed throughout the cerebral cortex and cerebellum of an affected proband, expanding our understanding of mechanisms attributed to primary microcephaly.

cytokinesis, neurogenesis, primary microcephaly, lissencephaly, autosomal recessive, citron kinase, splicing mutation

Reference: American Journal of Human Genetics, Volume 99, Issue 2, 4 August 2016, Pages 501-510 and 511-520, doi:10.1016/j.ajhg.2016.07.004 and doi:10.1016/j.ajhg.2016.07.003

The research was funded by the National Institutes of Health (HD069624) and several sources of funding in France. Full lists of authors and funding sources are available at the links above.
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Aug 12, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Zika mosquito

All forms of microcephaly may be linked to the protein citron kinase (CIT).
Image Credit: Centers for Disease Control and Prevention



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