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Mini brains: on the trail of malformations

Brain organoids provide new insights into human brain development. They also open up a view of the development of various diseases.

Human pluripotent stem cells, which are cultivated as 3D aggregates in a cell culture dish with nutrient liquid, have the ability to self-organize and develop into so-called brain organoids. Under the microscope, these brain organoids show structures that are very similar to the brain in its development phase. Brain organoids therefore represent an attractive new model system to study the development and developmental disorders of the human brain.

In a recent study by the Hector Institute for Translational Brain Research (HITBR) at the Central Institute for Mental Health (ZI) in Mannheim, researchers investigated how mutations in a single gene, the EML1 gene, can lead to a rare congenital malformation of the brain. Patient-derived or genome-edited brain organoids created in petri dishes displayed features of human disease – such as mislocated progenitor cells and neurons – allowing identification of underlying molecular mechanisms causing the malformation. This study has now been published in the journal EMBO Reports released.

Mutation in the EML1 gene: Severe disorganization of the cerebral cortex

The human cerebral cortex is a complex organized structure consisting of different layers of neurons, which also have convolutions and sulci. Due to its complexity, the development of the human cerebral cortex is still part of intensive research. Malformations associated with defects in human cortical development can lead to disorganization of the cerebral cortex with serious consequences such as epilepsy and intellectual disability.

Using brain organoids as a model for human brain development, HITBR scientists investigated how mutations in the human echinoderm microtubule-associated protein-like 1 (EML1) gene can lead to severe cerebral cortex disorganization and enlarged brains in patients. “Interestingly, brain organoids derived from EML1 patients reveal misplaced progenitor cells and neurons, recapitulating what is observed in the brains of patients,” explains Ammar Jabali, PhD student and first author of the study. “Based on this, we were able to investigate the molecular changes underlying this phenomenon.”

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Misplaced progenitor cells exhibit altered behavior

The researchers around the HITBR group leader Dr. Julia Ladewig produced brain organoids from stem cells that either came from EML1 patients or from stem cells in which they switched off the EML1 gene. In brain organoids, the cells self-organize—much like they do during embryonic brain development; Stem cells divide, some of the daughter cells develop into nerve cells; these migrate to specific locations where they eventually integrate into neural circuits. These are highly organized processes that eventually lead to a complex tissue.

These processes are disrupted in EML1 patients. “We were able to show that the progenitor cells show impairments in the primary cilia, a cell organelle that is important for anchoring the progenitor cells in a specific position. In addition, these cells showed altered division patterns. As a result, they move to places where they don’t belong,” explains Dr. Julia Ladewig.

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Furthermore, the researchers determined by means of single-cell gene expression analyzes that the misplaced progenitor cells also have altered gene expression patterns. “These misplaced cells, which have altered gene expression signatures, cannot be found in healthy control-derived brain organoids. These results support the idea that organoids can contribute to the understanding of normal and abnormal development of the human brain,” says Prof. Philipp Koch, head of HITBR.

Hippo signaling pathway as a key factor in massive growth

In order to understand how the misplaced cells multiply, the working group led by Dr. Ladewig possible affected signaling pathways. “Based on the recent scientific literature, the Hippo signaling pathway – a conserved signaling pathway that controls cell division and organ growth – has become a promising candidate that is a key factor in the observed massive expansion,” says Ammar Jabali. In fact, the researchers at HITBR were able to modulate the Hippo pathway and thereby mitigate the phenotypic changes in the EML1-deficient brain organoids, bringing them closer to healthy development.

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The scientists emphasize that this study helps to understand fundamental aspects of human brain development and in particular which signaling pathways are affected in EML1 patients. This could help to identify new treatment options for diseases related to cortical defects in the long term.

This text is based on a press release from the Hector Institute for Translational Brain Research at the Central Institute for Mental Health, Mannheim. We have the original publication for you here and linked in the text.

Image source: David Clode, unsplash

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