Project

The role of the choroid plexus in neurodevelopment(al disorders)

Code
DOCT/012777
Duration
15 November 2024 → 21 September 2025 (Ongoing)
Doctoral researcher
Research disciplines
  • Medical and health sciences
    • Developmental neuroscience
Keywords
Neural organoids Choroid plexus BAFopathiën
 
Project description
 

The BAF complex, a key chromatin remodeler, regulates transcription, replication, and repair in a

cell-type-specific and spatiotemporally controlled manner. Mutations in core BAF subunits (SMARCC1,

SMARCA4, SMARCB1) cause BAFopathies, a group of neurodevelopmental disorders. While known

that SMARCC1 loss disrupts neural stem cell regulation, it remains unclear whether similar

dysregulation occurs in other BAF subunits, leading to abnormal neural development. To address this,

CHOPIN will use human 3D choroid plexus organoids to map cell-type-specific transcriptional

regulation and cerebrospinal fluid (CSF) diversity of BAF subunits across development. The choroid

plexus is a relevant research model since CSF influences neural stem cells. Building on this

foundation, we will examine noncoding regulatory mechanisms, focusing on developing and

perturbing gene regulatory networks to elucidate how BAFopathy variants influence the regulatory

network of neural stem cells in the choroid plexus. Additionally, we will explore whether EZH2

inhibition via tazemetostat—exploiting synthetic lethality between EZH2 and SMARCB1—can restore

BAFopathy-associated defects, hypothesizing a shared vulnerability across early subunits. Overall,

this project will deepen our understanding of the role of the BAF-complex in the choroid plexus

during neurodevelopment and disease and may contribute to the development of novel therapeutic

strategies for BAFopathies.

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