My research interest is how genetic/molecular changes can result in psychiatric diseases. We are analyzing the phenotypes and molecular mechanisms of the schizophrenia-related mutation using mouse models and organoids from human ES cell lines.
A crucial component in the formation and maintenance of all tissues is the extracellular matrix (ECM), providing scaffolds which tie tissues and organs in place. In both the developing and the mature tissue, the ECM undergoe constant remodeling. Evidence for the differential expression of ECM during gyrification pinpoints its potential role in shaping the folds of the cerebral cortex through both mechanical and molecular configurations. In Collaboration with Prof. Irit Sagi, Maayan's Project is devoted to unravelling the biomechanics of the ECM during the cortical gyrification in health and disease.
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
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.
In this study, the role of NDE1 in the developing brain is investigated with different human brain organoids systems. Organoids which arise from NDE1 KO embryonic stem cells line are considerably smaller and grow slower than control organoids. In addition, in an on-chip method that allows the study of folding, the KO organoids exhibit a smoother surface than control organoids. Overall, the established NDE1 KO organoids exhibit features of microlissencephaly phenotypes.
Fate change as a novel mechanism of microcephaly: To uncover the molecular variations between the NDE1 KO organoids, RNA sequencing and q-PCR experiments were performed using different organoid cultures. A shift in cell fate was observed: (1) some of the organoids expressed higher levels of genes associated with caudal brain regions such as the cerebellum and the midbrain; (2) The expression of rostral markers was reduced in most of the experiments; (3) in some organoids both the changes occurred.
The observed change in cell fate may offer insights into a novel mechanism for microcephaly. The rostral part of the neural tube, which develops into the telencephalon is widely expanded in humans, whereas the caudal regions are smaller, thus reflected in smaller organoids.
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.
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.