For neurons, where they start is not necessarily where they end

The making of a human brain remains a largely mysterious process that goes from an embryonic neural tube to more than 100 billion interconnected neurons in the brain of a newborn. To achieve this marvel of biological engineering, the developing fetal brain must grow, on average, at a rate of approximately 250,000 nerve cells per minute throughout a pregnancy.

These nerve cells are often generated far from where they will eventually reside and function in the new brain, a migration that, although much studied in animal models using chemical or biological tracers, has never been studied directly in humans. ‘male. Until now.

In a new article, published online April 20, 2022 in Naturescientists from the University of California, San Diego School of Medicine and the Rady Children’s Institute of Genomic Medicine describe new methods to infer the movement of human brain cells during fetal development by studying recently healthy adult individuals died of natural causes.

“Each time a cell divides into two daughter cells, by chance one or more new mutations appear, which leave a breadcrumb trail that can be read by modern DNA sequencers,” said lead author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and Director of Neuroscience Research at the Rady Children’s Institute for Genomic Medicine.

“By developing methods to read these mutations in the brain, we are able to reveal key information about how the human brain forms, compared to other species.”

Although there are 3 billion DNA bases – and more than 30 trillion cells in the human body – Gleeson and his colleagues focused their efforts on a few hundred DNA mutations that likely arose during early divisions. cells after fertilization of the embryo or during early brain development. By tracking these mutations throughout the brains of deceased individuals, they were able to piece together the development of the human brain for the first time.

To understand the type of cells displaying these breadcrumb mutations, they developed methods to isolate each of the major brain cell types. For example, by profiling mutations in excitatory versus inhibitory neurons, they confirmed the long-held suspicion that these two cell types are generated in different germinal areas of the brain and then later mix in the brain. cerebral cortex, the outermost layer. of the organ.

However, they also found that the mutations found in the left and right sides of the brain were different from each other, suggesting that – at least in humans – the two cerebral hemispheres separate during development much earlier than we didn’t think so before.

The findings have implications for certain human diseases, such as refractory epilepsies, where patients present with spontaneous seizures and require surgery to remove a cerebral epileptic focus, said Martin W. Breuss, PhD, former project scientist at the ‘UC San Diego and now an assistant professor at the University of Colorado School of Medicine.

Breuss is co-first author with Xiaoxu Yang, PhD, postdoctoral researcher and Johannes CM Schlachetzki, MD, project scientist, both at UC San Diego; and Danny Antaki, PhD, former postdoctoral researcher at UC San Diego, now at Twist Biosciences.

“This study,” the authors said, “solves the mystery of why these foci are almost always confined to one hemisphere of the brain. Applying these findings to other neurological conditions could help scientists understand more mysteries of the brain.

Co-authors include: Xin Xu, Changuk Chung, Guoliang Chai, Valentina Stanley, Qiong Song, Traci F. Newmeyer, An Nguyen, Beibei Cao, Jennifer McEvoy-Venneri, and Brett R. Copeland, all at UC San Diego and Rady Children’s Institute for Genomic Medicine; Addison J. Lana, Sydney O’Brien, Marten A. Hoeksema, Alexi Nott, Martina P. Pasilla, Scott T. Barton, and Christopher K. Glass, all at UC San Diego; Shareef Nahas, Lucitia Van Der Kraan, and Yan Ding, Rady Children’s Institute for Genomic Medicine, and the NIMH Brain Somatic Mosaicism Network.

Funding for this research came, in part, from the Howard Hughes Medical Institute, the National Institute of Mental Health (grants MH108898, RO1 MH124890, R21 AG070462), the National Institute on Aging (grants RF1 AGO6106-02, R01 AGO56511-02 , R01 NS096170-04) and the IGM Genome Center at UC San Diego (S10 OD026929).


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