Neurodevelopmental disorders affecting human cognition
Normal neuronal differentiation and circuit formation in the brain are necessary for the development of cognitive function and are often disrupted in neurodevelopmental disorders such an intellectual disability, autism and brain malformations. Our research goal has been to understand the cellular and molecular mechanisms of human disorders that affect neuronal differentiation by identifying causative genetic mutations and developing appropriate animal models of disease in both mouse and zebrafish. The long-term research goal of the Manzini lab is to study the genetics and biology of cognitive disorders exploring the mechanisms of glycosylation and intracellular signaling.
Sex-specific intracellular signaling deficits in ASD/ID
Intellectual disability (ID) and autism spectrum disorder (ASD) affects up to 1:50 and 1:66 individuals in the US population, most frequently males, and ASD and ID are found together in up to 50% of cases. A large portion of cases are caused by a vast array of genetic mutations and by identifying the genes involved in ASD/ID, we can begin to make sense of this extreme heterogeneity. By defining whether common signaling pathways are involved, we can determine whether patients can be classified according to gene function. Dr. Manzini studied families affected by different forms of ASD/ID and identified novel loss-of-function mutations in the CC2D1A gene, which when mutated causes a spectrum of neuropsychiatric disorders including severe ID, ASD and seizures. CC2D1A is involved in trafficking of various transmembrane receptors and in the regulation of receptor signaling to the nucleus. In developing a mouse where Cc2d1a is removed in the brain we discovered a remarkable sex-specificity in Cc2d1a function, leading to more severe behavioral impairment in male. We are currently exploring how sex-specific intracellular signaling is established using biochemistry and advanced microscopy in mice and human induced pluripotent stem cell (iPSC) models to determine whether it contribute to the sex bias in ASD and ID.
Understanding the role of the extracellular matrix in brain and muscle
The extracellular matrix (ECM) is a meshwork of proteins and polysaccharides residing in close opposition to the cell membrane. Originally thought to play a simple structural role, the ECM is emerging as an important regulator of diverse aspects of cellular differentiation, from proliferation to cell death. The ECM can act directly by binding to receptors on the cell surface or indirectly by trapping and presenting local guidance cues and growth factors to the cell. Mutations in genes encoding ECM components such as laminins and collagens as well as cellular ECM receptors and enzymes involved in ECM receptor glycosylation cause a spectrum of disorders characterized by congenital muscular dystrophy (CMD) and brain malformations. The variety of affected genes suggest that these ECM proteins must act together or in parallel pathways to control brain and muscle development, but the exact mechanisms are unknown. As novel therapies are being developed for muscular dystrophy, it is critical to understand how they may affect the brain.
This project focuses on the identification of novel disease genes in families affected by these disorders and then replicates the disease in animal models (zebrafish and mouse) with the dual goal to 1) study the mechanisms underlying disease and 2) explore the biological function of the disease genes in cognitive development. By developing multiple models of disease we are also aiming at testing how newly developed therapies will affect the muscle and the brain.
This project focuses on the identification of novel disease genes in families affected by these disorders and then replicates the disease in animal models (zebrafish and mouse) with the dual goal to 1) study the mechanisms underlying disease and 2) explore the biological function of the disease genes in cognitive development. By developing multiple models of disease we are also aiming at testing how newly developed therapies will affect the muscle and the brain.
