Research

Bidisha's Project: The role of CUL4B in neural progenitor development and brain patterning

CUL4B is implicated in brain disorders, including cortical malformations and intellectual disabilities. This study investigates how CUL4B mutations disrupt brain development using developing mouse brains and human brain organoids. Loss of CUL4B impairs the growth and timely division of neural progenitor cells, causing cell-cycle delays, premature differentiation, and reduced neuron production. These defects also alter the maturation and regional identity of developing brain structures. At the cellular level, these abnormalities may arise from disrupted CUL4B-dependent regulation of the cell’s internal architecture, providing insight into how CUL4B mutations contribute to neurodevelopmental disorders.

Shai's Project: HNRNPU mutations and their impact on cortical development

The heterogeneous nuclear ribonucleoprotein U (HNRNPU) gene encodes a widely expressed nucleoplasmic protein that binds DNA and RNA, interacts with the nuclear matrix, organizes chromatin, regulates gene accessibility, and participates in transcription. Like other HNRNPs, it can enhance or repress splicing in a context-dependent manner. Heterozygous, often de novo mutations in HNRNPU are associated with a neurodevelopmental disorder (NDD) characterized by intellectual disability, developmental delay, epileptic seizures, and craniofacial dysmorphism. We hypothesize that phenotypes in this disorder stem from an excitation-inhibition imbalance in the developing brain. Using advanced organoid models, we aim to identify the underlying molecular processes in HNRNPU mutants that disrupt cortical development and alter the excitation-inhibition balance, paving the way for new therapies for HNRNPU-related NDD.

Boaz's Project: modelling of early familial Alzheimer's Disease in organoids

Different mutations linked with familial Alzheimer's Disease (fAD) react through different pathways to induce fAD in patient brains. We aim to characterize the early stages of fAD in human models, which are currently lacking in bio-medical research. By combining a broad range of genome-editing techniques, we can characterize the pathogenicity of different fAD mutations in region-specific cerebral organoids, with the addition of other components such as microglia.

Motivated MSc students who are interested in taking part or hearing additional details about my work are more than welcome to contact me Boaz.Yaari@weizmann.ac.il

Svetlana's Project: Modelling NDE1 derived pathogenic mutations

NDE1 is a gene that encodes a member of the nuclear distribution E (NudE) family of proteins. NDE1 is part of a multiprotein complex that controls the function of the molecular motor cytoplasmic dynein. The protein localizes to centrosomes and is involved in neuronal migration, mitosis, and intracellular transport. A recent missense point mutation, S214F, was discovered among schizophrenia patients and is believed to affect the developing brain at a molecular level by forming abnormal interactions with other proteins and altering myelination, which may have implications in the context of psychiatric diseases but is yet an understudied topic. This research examines the possible contribution of NDE1-S214F mutation to schizophrenia- predisposition in the molecular, cellular, tissue, and organism levels. We will combine human organoids with mouse models to accomplish this, providing a powerful tool for studying the pathophysiology of neurodevelopmental diseases.

Rami's Projects: From neuroepithelium to neurogenesis

NDE1 KO organoids exhibit microlissencephaly phenotypes: Human malformations of cortical development (MCDs) are rare disorders, which have been associated with conserved brain architecture with fewer neurons (microcephaly) or associated with absent or abnormal gyri (lissencephaly). A more severe disorder is microlissencephaly, in which both the size and the folding pattern of the brain are affected, and results from a loss of function of the NDE1 gene.

Itay's Project: Metabolic Organelles in Human Models of Neurodegenerative Diseases

The brain tissue is sensitive to metabolic stress, which might contribute to progression of different Neurodegenerative Diseases (NDs). In my study, I am focusing on cellular metabolic organelles, such as Mitochondria and Lysosomes.