In search for new methods to explore hitherto hidden developmental events, Dr Eyal Karzbrun from our lab engineered a novel experimental brain modeling technique called "on-chip organoids", or "mini-brains". By limiting growth on the vertical axes, we can now record a range of events in mini brains derived from human embryonic stem cells. These days our group work hard to constantly improve the model and cherish the opportunities it introduces.
A crucial component involved 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 potentially fundamental role in shaping the folds of the cerebral cortex through both mechanical and molecular configurations. In Collaboration with Prof. Sagi lab, Maayan's Project is devoted to unravelling the biomechanics of the ECM during the cortical gyrification.
Lissencephaly ("smooth brain") and Rett syndrome are two developmental brain diseases, which so far have not been associated. Using biochemical and molecular methods, we revealed a novel protein-protein interaction between LIS1 and MeCP2, the mutated genes, respectively. Our studies reveal functional activities of LIS1 and MeCP2, and discover molecular mechanisms involved in regulation of MeCP2 in the nucleus. Overall, Liraz's Project aims to unravel these complex protein interactions to fascilitate the development of therapeutic treatments for associated human diseases.
Human mutations in the Rotatine (RTTN) gene result in a wide spectrum of cortical malformations, suggesting its importance in multiple aspects of brain development. In collaboration with Götz Lab, Vittoria and Rami's project aims to study RTTN-associated cortical malformations and to identify aberrant signalling pathways. Using hESCs mutated by CRISPR-Cas9 and iPSCs derived from patients, Human ‘on chip’ brain organoids will be generated and used.
Main: Human malformations of cortical development (MCDs) are rare disorders, which can be associated small brain (microcephaly), and/or with neuronal disorganization and absent of abnormal gyri (lissencephaly). Rami's main project focuses on the NDE1 (Nuclear Distribution Element 1) gene, found to be mutated in patients with microlissencephaly. With our human brain organoids, the effect of the NDE1 on brain folding, size, and upon other genes, is investigated.
But also..: So far, our novel organoids systems focused on the earliest neuroepitillium developmental stage; when neurons are yet to be born. One part of Rami's work is to allow neurogenesis in this system, and thus enable the investigation of later human brain development events.
Aditya's project is focused on understanding the functions of LIS1 in relation to how cell identity is established, maintained, and altered during early mammalian development. Specifically, molecular control of embryonic stem cell (ESC) pluripotency and transition during early development to neural lineages. I am using multi-omics approaches in mESCs and human brain organoid models to study protein-protein interaction and regulatory networks that govern ESC pluripotency and neuronal fate transition, to get mechanistic insights into Lissencephaly and neurodevelopmental disorders associated etiology.