Development of the Primary Olfactory Pathway

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The long term aim of this project is to identify axon guidance molecules involved in establishing the complex topography of the primary olfactory pathway. We previously identified critical time points in development where axon behavior indicates that guidance molecules are acting. Olfactory sensory neuron (OSN) axons grow from the olfactory placode to the telencephalic vesicle in early embryonic development. Axons penetrate the telencephalon, forming a presumptive olfactory nerve layer (pONL). A small subset of axons grow to the ventricular surface which has been suggested to induce the formation of olfactory bulb (OB). The majority of axons remain restricted to the pONL for up to 4 days, presumably sorting out into molecularly defined subsets. After 4 days, some axons grow deeper into the OB, initiating glomerular formation. A pivotal question in understanding olfactory pathway formation is which cue(s) are present in the OB that prevent(s) axon ingrowth prior to glomerular formation? One way to answer this key question is to examine the distributions of candidate guidance molecules within the developing pathway. We hypothesize that the stalling of axons within the pONL may be due to inhibitory guidance molecules within the developing OB. One potential source of inhibitory cues in the OB are components of the extracellular matrix (ECM). We have identified members of the tenascin and chondroitin sulfate proteoglycans (CSPGs) as good candidates for the inhibitory cues that regulate axon ingrowth and glomerular formation. The specific aims of the current proposal are to: 1) test the hypothesis that components of the ECM are key regulators of OSN axon spatio-temporal dynamics in the developing olfactory pathway, and to functionally test the ability of these molecules to inhibit OSN neurite outgrowth in vitro;2) to test the hypothesis that both integrin and non-integrin ECM receptors facilitate cell surface - matrix interactions in the developing olfactory system and to functionally test their ability to modulate OSN neurite outgrowth on ECM substrates in vitro;3) to test the hypothesis that the matrix metallooroteases play an important role in sculpting the ECM environment during development of the olfactory system. These studies will greatly enhance our knowledge of how axons establish connections in the olfactory system and may have implications for diseases such as Kallman's syndrome. Moreover these results will be broadly applicable to other CNS regions where work continues towards understanding the formation of boundaries and topographic maps.