Elucidation of the complex pathways which shape brain development for understanding the pathogenesis of mental retardation and congenital brain malformations. Perturbation of dorsal-ventral patterning, the process by which the dorsal and ventral regions of the brain become morphologically and functionally distinct, can result in brain malformations. For example, holoprosencephaly, a severe brain anomaly, arises from either over- expression of dorsally acting factors or lack of ventral-inducing activity. The bone morphogenetic proteins (BMPs) are the major inducers of dorsal identity in the developing nervous system. However, little is known regarding the distribution of the BMP receptors (BMPRs) or their role in dorsal-ventral patterning of the brain. We hypothesize that abnormal BMP receptor activity will disrupt patterning and lead to brain malformations. We will study the effects of constitutively active and dominant negative constructs of the BMPRs on the developing brain of the chick embryo. During the current award period, we have determined that the BMPRs are expressed in a dynamic pattern in the nervous system, beginning at very early embryonic stages. Message was present in specific regions of the brain and dorsal spinal cord, consistent with the role of the BMPs in dorsal induction of the neural tube. We expect that these BMPR constructs with altered activity will perturb normal brain development. In this proposal, we will analyze the brains expressing the abnormal BMPR constructs in several ways. First, we will analyze the brains expressing the abnormal BMPR constructs in several ways. First, we will delineate the morphologic abnormalities caused by the constructs. Second, changes in genetic patterning will be assessed by identifying the altered expression of genes normally expressed only in specific regions of the brain. Third, changes in the functional connections of neurons will be examined. These studies will provide insights into both normal brain development and the pathogenesis of brain anomalies and developmental disabilities.
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