Head size and Autism

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Variations in the 16p11.2 region of the genome are associated with autism spectrum disorder. While people with genetic deletions in this region have larger heads (macrocephaly) and people with genetic duplications have smaller heads (microcephaly), both variation types affect brain development and function.

To study the effects of these variations and search for ways to minimize their impact, University of California San Diego School of Medicine researchers are using brain organoids — tiny, 3D cellular models generated in the lab from people with 16p11.2 variations.

The organoids, described in a paper publishing August 25, 2021 in Molecular Psychiatry, mimicked the differences in brain size seen in people. They also revealed new information about the molecular mechanisms that malfunction when the 16p11.2 region of the genome is disrupted, providing new opportunities for potential therapeutic intervention.

Iakoucheva led the study with Alysson Muotri, PhD, professor of pediatrics and cellular and molecular medicine at UC San Diego School of Medicine.

The brain organoids were created using induced pluripotent stem cells derived from people who have 16p11.2 genomic variations — three people with deletions, three with duplications and three non-variant controls. Researchers obtained a skin sample from each person, gave the skin cells a molecular cocktail that converted them to stem cells, then treated the stem cells in a way that coaxed them into becoming brain cells, preserving each patient’s unique genetic background.

The organoids revealed that RhoA — a protein that plays a big part in many basic cellular functions, such as development and movement — is more active in both 16p11.2-deleted and 16p11.2-duplicated organoids than it is in organoids without these variations. Over-active RhoA led to a slowdown in neuronal migration, the process by which brain cells get to where they need to be for normal fetal development and function in adulthood.
When the team inhibited RhoA in the autism-like organoids, neuronal migration was restored to levels seen in the control organoids.

“Our work opens the possibility to therapeutically manipulate the RhoA pathway,” said Muotri, who is also director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine

Funding for this research came, in part, from the Simons Foundation for Autism Research and National Institutes of Health.