Specific MicroRNA Signatures in Brain Organoids Potentially Serve as Rett Syndrome Biomarkers

Rett syndrome, a rare genetic neurological disorder primarily affecting females, typically manifests after a period of normal early development. Over time, children with Rett syndrome experience a loss of motor skills, develop repetitive movements, and may face difficulties with walking and experience seizures. The disorder is caused by mutations in the MECP2 gene, which plays a crucial role in regulating gene activity in the brain.

Researchers have now identified distinct microRNA (miRNA) fingerprints within extracellular vesicles (EVs) produced by brain organoids mimicking Rett syndrome. These findings offer promising insights into the potential use of EV miRNAs as biomarkers for monitoring disease progression and evaluating the effectiveness of therapeutic interventions.

Using 3D organoids grown from human-derived stem cells with and without a severe MECP2 mutation, scientists at Maastricht University in the Netherlands created mini brain-like structures that recapitulate key aspects of brain development and function. These organoids allowed researchers to study the role of miRNAs in EVs, tiny particles released by cells that carry various bioactive molecules, including miRNAs, to facilitate communication between cells.

The team focused on examining EV miRNA profiles in dorsal and ventral forebrain organoids, regions thought to have distinct structural and functional alterations in Rett patients, over a period of 75 days, allowing nerve cells to mature and become fully functional.

Their analysis revealed 20 EV miRNAs present at significantly different levels in Rett organoids compared to controls. These miRNAs fell into three distinct groups based on their expression patterns over time.

Six miRNAs, belonging to a cluster called hsa-miR-302/367, showed a parallel decline in both dorsal and ventral regions of control organoids. However, in Rett organoids, four of these miRNAs exhibited significant differences compared to controls by day 75.

“The high EV expression of these miRNAs in the early stages of neuronal development might thus promote proliferation and the maintenance of [the development] of neighboring cells,” the researchers wrote.

Examining individual time points further revealed that the production of 29 EV miRNAs was either increased or decreased at least once in the ventral or dorsal organoids of Rett and control samples. More than half of these miRNAs belonged to a cluster called C14MC. All C14MC miRNAs showed higher expression in Rett samples compared to controls, with 30% reaching statistical significance.

The team noted that C14MC members are known to play a role in regulating genes critical for brain growth and development. Additionally, miRNAs in this cluster target signaling related to serotonin, a brain signaling molecule found at lower levels in the brains of Rett patients. Therefore, the increased levels of C14MC miRNAs in Rett may suppress serotonin pathways.

“Future studies could aim at validating our findings for other [Rett]-causing MECP2 mutations,” concludes the study. “Once validated, the C14MC miRNAs from biofluid-derived neuronal EVs have the potential to be used as biomarkers for monitoring Rett syndrome progression and the effect of intervention strategies.”

What are microRNA signatures and how might ‌they be used in diagnosing Rett syndrome?

## Mini-Brains Offer⁤ Hope for Rett⁤ Syndrome Diagnosis and Treatment

**Intro Music**

**Host:** Welcome back to the⁣ show. Today we’re discussing a promising ‌new development in the fight against Rett⁣ syndrome. Joining us is Dr. [Guest Name], ⁣a leading researcher in the field. Dr. [Guest Name], thanks for being here.

**Dr. [Guest Name]:** Thank you for having me.

**Host:** ‍ Now, for ⁣our viewers‌ who ‍may not be familiar, could you briefly explain what Rett syndrome is?

**Dr. [Guest Name]:** Rett syndrome is a rare genetic disorder‌ that⁣ primarily affects females. It typically manifests after a child’s development appears ⁤normal‍ for‍ the first few months or years of ⁢life. As they grow, children with Rett syndrome experience a heartbreaking regression, losing motor skills, developing ⁢repetitive movements, and ⁣facing​ challenges with walking ‍and seizures.

**Host:** That sounds incredibly difficult for families to ‍cope with. What causes this⁣ devastating condition?

**Dr. [Guest Name]:** Rett syndrome is caused by mutations in a gene called MECP2. This gene plays a critical role in regulating other genes in the brain, so when it malfunctions, it can have a profound impact on brain development and function. [[1](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005386/)]

**Host:** Your research team has made some exciting breakthroughs using “brain⁤ organoids” – can you⁤ tell us‌ more about this?

**Dr. [Guest Name]:** We’ve been using 3D organoids, which are essentially mini-brains ⁤grown from human-derived stem cells. Our lab is focused‌ on creating organoids that mimic the brain characteristics of Rett syndrome. ‍This allows us to study the disease in a controlled environment⁢ and explore potential treatments.

**Host:** ​ And what have you discovered through this research?

**Dr. [Guest Name]:** We’ve found distinct patterns ‍of microRNAs – tiny⁤ molecules ⁤that regulate gene expression – within extracellular vesicles, or EVs, produced ‌by these Rett syndrome organoids. These ‘fingerprint’ patterns of microRNAs could potentially serve as biomarkers for Rett syndrome.

**Host:** That’s fascinating. What ‍does that mean for families affected by Rett syndrome?

**Dr. [Guest Name]:** This could be a game changer.

Identifying these unique miRNA signatures in EVs can lead to earlier and more ⁣accurate​ diagnosis of Rett ⁤syndrome.

Furthermore, these biomarkers could help us monitor​ the progression of the disease and ⁢evaluate⁣ the‌ effectiveness of potential therapies.

**Host:** That’s incredible news! Where do you see this research going next?

**Dr. [Guest Name]:** We are now working⁣ to validate these findings in⁤ patients with Rett syndrome and explore the potential of using these biomarkers in clinical settings.

The ultimate goal ‍is to develop targeted therapies that can improve the lives of ​individuals living with Rett syndrome.

**Host:** Thank ⁣you so much for sharing your insightful work with us Dr. [Guest Name]. We wish you and your team all the best in finding effective treatments for Rett syndrome.

**Outro​ Music**