Polarity Signals Coordinate Neuronal Differentiation & Nuclear Organization

Project Summary Abstract: During neural development, billions of nerve cells go through a highly orchestrated sequence of differentiation, migration, and forming connections with other neurons. Our recent research has shown that proteins involved in controlling the directionality of neuronal migration also have a role in controlling the organization of chromatin in the cell nucleus, which is linked to neuronal differentiation. This exciting discovery could lead to a better understanding of developmental disorders and pediatric cancers where neuronal differentiation is compromised. Our previous research demonstrated that two specific proteins, Pard6a and Pard3, play a crucial role in neuronal development in the cerebellar granule neuron and are antagonized by another protein, Siah2, which is present in neuronal precursors. Our latest findings have shown that neuronal precursors compact their chromatin and that Pard6a and Siah2 are surprisingly located in the nucleus during neuronal development. Loss or gain of these proteins can significantly impact chromatin compaction. This suggests that the proteins involved in controlling neuronal polarity in migration and adhesion are directly linked to changes in chromatin organization during neuronal development. This work implies a premise that polarity signaling directly links nuclear reorganization to neuronal differentiation. We will build on our polarity signaling expertise to mix in vivo genetics and ex vivo mechanistic studies with transformative single-cell imaging technologies to explore these aims: Aim1: Define how Siah2 restrains CGN nuclear condensation and chromatin compaction. Aim 2: Define how Pard6a promotes CGN nuclear condensation and chromatin compaction. We will use advanced imaging technology, in vivo genetics, and ex vivo mechanistic studies to explore these findings further. If successful, this research will provide a new conceptual model of how neuronal differentiation promotes chromatin compaction and nuclear condensation. Enhancing our fundamental knowledge of these basic cell biological processes in neurodevelopment can lead to new diagnostics or treatments for neurodevelopmental disorders and pediatric cancers where neuronal differentiation is compromised.