Grant: Operating Grant

The ability of cells to polarize is critical for complex biological activities, such as the organization of a fully functional nervous system. The functional units of the nervous system, the neurons, are an exquisite example of highly differentiated and polarized cell types; typically extending a long thin process called axon, which is engineered to propagate signals, and several shorter and thicker processes called dendrites, which are designed to receive signal inputs. The asymmetric localization of proteins within the axons and dendrites is crucial for a neuron to develop its fully functional architecture, but how the axonal and dendritic compartments are specified remains unclear. The major question that we are going to address in this project is how is the characteristic morphology of neurons acquired? Specifically, we will focus on the function of a recently identified gene, called Inscuteable (Insc), on the process of axonal specification. Recent studies, mostly conducted in invertebrates, have shown that Insc is part of an important polarity complex that regulate cellular function in various cell types, but its role in neuronal cells remain unknown. Here, we propose to use a combination of mouse genetic and cell biology approaches both in vitro and in vivo to determine the function of Insc in mouse neurons. We will test the hypothesis that Insc is involved in the specification of axons and dendrites in neurons, and that disruption of Insc activity leads to the formation of abnormal neurons. Based on mouse and human genome sequence data, no other gene was duplicated from the invertebrate Insc ancestor, suggesting that loss of Insc will lead to potent defects when inactivated in mouse, or when mutated in humans. Our work should help identify key developmental defects caused by Insc loss of funtion, which could lead to identification of similar conditions in humans with Insc mutations.