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Developmental biology - Brain Gene
A Gene That Helps Define Us As Humans
There is a gene that sets primates - great apes and humans - apart from other mammals...
Through the study of a rare developmental brain disorder, researchers have discovered a gene that sets primates - great apes and humans - apart from other mammals. Adam O'Neill carried out his research at the University of Otago, in Dunedin, Otago, New Zealand in the laboratory of Professor Stephen Robertson. O'Neill's discovery is that the PLEKHG6 gene drives aspects of brain development differently in humans than in other primate species.
"Broadly speaking, the PLEKHG6 gene can be thought of as one of the genetic factors that make us human in a neurological sense."
Adam O'Neill, post doctural student, Department of Physiological Genomics, Ludwig Maximilian Universität in Munich, Germany, explains.
Stephen Robertson PhD, believes this research, just published in the internaprofessortional journal Cell Reports, is the human gene that made our brains bigger and better functioning - in some respects - than in other animals. However, this increased complexity might have come at a cost, potentially predisposing us to a whole suite of neurological and psychiatric conditions.
"Such genes have been hard to find, but using an approach in which we studied children with a certain brain malformation called periventricular nodular heterotopia, we found a 'damaged' gene element in a child with attributes of just such a primate specific gene," Robertson explains. In periventricular heterotopia a subset of neurons in the developing brain fail to locate in their correct position in the brain, resulting in a variety of symptoms including epilepsy and delayed development.
O'Neill and research collaborators from Max Planck Institute of Psychiatry in München Germany, tested how the PLEKHG6 gene drives aspects of brain development unique to primates. They did so using stem cells converted into human brain organoids or "mini-brains". In culture, the mini brains showed how the PLEKHG6 gene altered the ability and growth of proliferating stem cells. Some of these cells failed to migrate into their correct position in the first few weeks of development.
Robertson makes the point that it is known mini brain stem cells behave differently between primates, but understanding which genes regulate these differences was the mystery.
"Adam's achievement shows us this particular component of the PLEKHG6 gene is one regulator that humans 'acquired' very recently in their evolution to make their brains 'exceptional.'"
Stephen P. Robertson PhD, Department of Women’s and Children’s Health, University of Otago, Dunedin, New Zealand.
O'Neill says there are very few primate specific genes in our genome, so this discovery adds to a very short list of genes making us human.
O'Neill: "We need to better understand how a brain builds itself - knowledge that increases our ability to repair damage, especially early in infancy where there are still lots of stem cells around." The work also provided more information about genes that are altered and causing this particular brain malformation.
"I think it underscores how very subtle differences separate us from other animals. We should be much more humble."
Adam O'Neill, postdoctural candidate
Highlights
• Excess variants within basal radial glia transcriptomic signatures in cases of PH
• PLEKHG6 primate-specific isoform mutated in a case of PH functions via RhoA
• PLEKHG6 isoforms regulate features of neurogenesis
• Modulation of the PLEKHG6 primate isoform reproduces features of PH in organoids
Summary
The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development.
Authors
Adam C. O’Neill, Christina Kyrousi, Johannes Klaus, Magdalena Go¨tz, Silvia Cappello and Stephen P. Robertson.
This work was supported by Curekids and the Health Research Council of New Zealand.
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Dec 7, 2018 Fetal Timeline Maternal Timeline News News Archive
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