Laboratory of Neurogenetics and Development
Laboratory of Neurogenetics and Development The research in my laboratory centers on discovery of gene mutations associated with brain malformations and investigation of how these genes direct the construction of brain. Three major projects encompass: 1) neural tube formation, 2) cell cycle regulation and its role in cellular patterning of brain, and 3) regulation of neuronal migration to establish brain architecture. These three areas of study, all NIH funded, are approached from both basic science and clinical genetic perspectives.
Neural tube closure -- This project examines mechanisms leading to neural tube defects (NTDs) and their prevention by folic acid and other agents. We previously modeled human NTD prevention by folic acid supplementation in the Crooked tail (Cd) mutant mouse line and showed Cd to be a remarkably good paradigm for investigation of the vitamin's effects on brain development. We identified the Cd gene mutation as defect in the Lrp6 co-receptor that is required for Wnt signaling, a key pathway in early development and tumor formation. The roles of Wnt pathway components in cellular and molecular events leading to NTDs and cortical dysplasia are studied. This work is being extended to a multi-center clinical effort to examine complex genetic traits associated with NTDs, using folate pathway and other candidate genes to screen clinical populations.
Neurogenesis -- Primary genesis and differentiation of neurons are examined in the context of cell cycle regulation and its relationship to brain structure. We have shown that the G1 active protein, cyclin D2, is expressed in developing mammalian brain in highly specific and restricted brain regions. Our studies of animals lacking cyclin D2 expression demonstrated that this isoform is necessary for the emergence and survival of cerebellar stellate interneurons, half of the granule cell population, and specific cerebral interneurons. Ongoing work addresses how molecular components of the cell cycle are controlled to generate specific neurons and whether this activating subunit of cyclin dependent kinases has a direct role in the differentiation of selected neuronal precursors. Recent investigations are using mouse and human embryonic stem cells to study the role of cyclins in the specification of neural progenitors.
Neuronal migration -- This project aims to identify and study genes responsible for human brain malformations. This began with the linkage mapping and identification of a gene associated with an X-linked form of lissencephaly (XLIS/DCX). Using a mouse knockout of Lis1, a gene causing an autosomal dominant form of human lissencephaly , we have taken biochemical and cell culture approaches to examine neuronal motility and cytoskeletal regulation. Our studies have revealed that loss of Lis1 results in deregulated Rho-family GTPases and that Lis1 participates in molecular cascades that affect neuronal cytoskeletal dynamics to impact their movement and connections between neurons. In our emerging model, Lis1 is viewed as a signalling molecule required for the transduction of molecular cues presented to the neuronal surface to modulate migration and neuronal connectivity.
Dr. Ross is the Nathan Cummings Professor of Neurology and Neuroscience Director, Center for Neurogenetics Chair