Institute of Molecular Biotechnology Develops Organoid Model Showing Neuronal Development in Brain

The brain has many networks that can be likened to country roads with connections to nearby nerve cells, while the thick nerve bundles connecting to different brain regions are like highways. Researchers have developed a model that follows these nerve bundles.

Brain Model From the Institute of Molecular Biotechnology

Jürgen Knoblich at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences led a research team and collaborated with Gregor Kasprian and colleagues at the Medical University Vienna to develop an organoid model of nerve bundles.

"Organoids allow us to trace all steps in neuronal development and investigate them directly in human tissues," Jürgen Knoblich explained.

For the new study, the team worked with Yoshiho Ikeuchi at the University of Tokyo to model the connection between two brain hemispheres. Two brain organoids joined by a microchannel were inserted into a 3D-printed mold. The researchers saw how they were related through the two organoids' neural extensions or axons. The ARID1B alterations significantly impacted the connection.

Healthy organoids develop a well-organized bundle of axons connecting to numerous additional organoids. According to Nina Corsini, organoids with the ARID1B mutation also form similar bundles but have considerably fewer connecting axons.

The research team used information about a rare neurodevelopmental illness, in which the connection between the left and right hemispheres of the brain does not develop, to model the long-range, heavily used nerve bundles.

One bustling information highway in the brain is the corpus callosum, which connects the left and right sides. Rarely, though, does this link fail to emerge throughout development. This can be identified during the ultrasound screening around the 18th week of pregnancy.

According to Kasprian, in these situations, fetal magnetic resonance imaging (MRI) can be utilized to acquire an accurate image of the fetal brain in addition to the absent corpus callosum and any related anatomical abnormalities.

Clinical literature has extensively documented the correlation between a deficiency in ARID1B and the absence of the corpus callosum. However, according to Catarina Martins-Costa, the study's first author, nothing is currently known about the molecular pathways involved in this deficiency.

Thus, brain organoids with an ARID1B mutation represent the first model that thoroughly examines these crucial neural connections in the human brain. Clinical research can also greatly benefit from this progress.

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ARID1B Mutations Linked To Neurodevelopmental Disorders

Another study has linked mutations in the gene encoding AT-rich interactive domain-containing protein 1B (ARID1B) to several diseases, including nonsyndromic intellectual disability, developmental delay, and intellectual disability.

Although haploinsufficiency is expected to result from most of the Arid1B mutations found so far, the underlying pathogenic processes are still unclear. The Brahma-associated factor chromatin remodeling complexes, essential for controlling gene activity, contain the DNA-binding component ARID1B. Subunit composition can control the activity of remodeling complexes, and there is evidence that ARID1B is part of the neuron-specific chromatin remodeling complex. This complex mediates the regulation of stem/progenitor cells exiting the cell cycle and developing into postmitotic neurons.

Reduced amounts of wild-type protein impair normal brain development, and RID1B is connected to neurodevelopmental disorders. It is also expected to play a significant role in neurodevelopment.

The mechanisms by which compromised brain development leads to intellectual disability and speech impairment. They are regularly seen in people with ARD1B haploid insufficiency, which needs further investigation.