Discovery of a gene essential for brain development
Magnetic resonance imaging (MRI) images of a normal mouse on the left, with the presence of the corpus callosum in red, and abnormal on the right, characterized by the absence of the corpus callosum. This non-invasive technique allows researchers to detect perturbations in the overall organization of the brain, particularly abnormalities in communication between the two hemispheres. By Chrystelle Po (ICube, University of Strasbourg, CNRS, FMTS, Strasbourg, France)
Proc Natl Acad Sci U S A Oct. 12, 2017
Oct. 18, 2017
Cognitive diseases represent 5 to 10% of public health costs, yet their genetic and biological causes remain incomplete. Binnaz Yalcin’s team uncovered a major role of the WDR47 gene in the development of the brain, in particular in the formation of the corpus callosum, an important brain structure involved in communication between the two hemispheres but also in memory processes, learning and laterality. This study also revealed the involvement of WDR47 in the regulation of autophagy in the brain, a cellular mechanism that allows neurons to eliminate their own toxic components by digesting them. These results are published on 9th October 2017 in the journal PNAS
Through collaboration with the Sanger Mouse Genetics Project (UK), Binnaz Yalcin’s team studied brain’s anatomy from 26 mouse lines each carrying a different WDR gene mutation, and found that seven of these genes are associated with anomalies in the corpus callosum, either too thick, too thin or even outright absent in the case of the mutation of the WDR47 gene. The researchers focused on the study of this single gene.
WDR47, essential for mouse survival, brain development and certain behaviors
By modulating gene expression in different models of mutant mice, researchers have shown that the more the WDR47 gene is expressed, the better the chances for the mouse to survive. Moreover, the inactivation of the WDR47 gene leads to various brain malformations, including a smaller brain size from 25%, called microcephaly, with a concomitant decrease in nerve fibers. In collaboration with Juliette Godin's team at the IGBMC, researchers have demonstrated that the microcephaly observed in adult mice starts from the embryonic stage with a decrease in the number of neurons produced and an increase in their death just before birth.
To understand why the corpus callosum was not properly formed, scientists used super-resolution microscopy techniques, which showed that in the absence of WDR47, nerve fibers lacked their growth cone, a structure present at their tip which serves as a guide for proper movement during their growth. When visualizing these growth cones, the researchers also observed instable microtubules, kind of rails allowing the fibers to move properly. The administration of a microtubule-stabilizing drug corrects the defects of these cells, demonstrating the role of the WDR47 protein as a regulator of microtubules stability and as a regulator of growth cone formation.
The researchers also observed that in the absence of the corpus callosum, mice show a significant decrease in dexterity, muscle strength and coordination of their limbs, hypersensitivity to pain and locomotor hyperactivity.
Region of the WDR47 protein associated with waste recycling in the cell
After having demonstrated the major role of WDR47 in mouse brain development, the team of Binnaz Yalcin, in collaboration with Sylvie Friant, University of Strasbourg, obtained consistent results in yeast. The researchers also showed that when WDR47 is overexpressed, the yeast culture did not grow. This difference relates to a small biological sequence of the WDR47 protein, which has been associated in yeast with the mechanism of waste recycling essential to the proper functioning of the organism. Together, these results provide a better understanding of the genetic basis of brain development and related disorders, with the ultimate aim to improve the clinical diagnosis and treatment of patients with these brain malformation disorders that Binnaz Yalcin’s team named "WDRopathies".
This study was funded by the ANR, the foundation Jérôme Lejeune, the Labex (University of Strasbourg) and the Gutenberg circle.