Kallmann's syndrome is a hereditary developmental disorder characterized by anosmia and gonadotropin-releasing hormone (GnRH) deficiency. Normally during development, olfactory neurons arise from the nasal epithelium and extend their axons to the ventral edge of the nascent telencephalon. The axons pause, during which time they induce formation of the olfactory bulb, and then enter to synapse with the mitral cells. GnRH cells are also born in the nasal epithelium, and migrate into the brain in association with olfactory-derived axons. In Kallmann's syndrome, olfactory axons and GnRH cells reach but do not enter the brain.
The protein that is missing or mutated in the X-linked form of Kallmann's syndrome is known, but not why its absence produces the phenotype. This thesis focuses on elucidating mechanisms governing olfactory axon pathfinding, with the specific goal of determining the function of Kal protein. In order to test the hypothesis that Kal acts as a guidance factor for olfactory axons and GnRH cells, in vivo and in vitro experiments were performed, in chick and mouse, respectively.
Kal is expressed in chick mitral cells, but not in nasal epithelium or olfactory axons. In an attempt to induce aberrant axon pathfinding, Kal was misexpressed in chick olfactory axons. No significant effect was observed. It may be that the effect of chemorepellent semaphorin-3A (sema-3A) overrode ectopic expression of Kal protein. Sema-3A is expressed in the peripheral telencenphalon and prevents olfactory axons from entering the forebrain before olfactory bulb differentiation: expressing a dominant-negative receptor of sema-3A in olfactory axons caused those axons to enter the forebrain early and overshoot their target.
To pursue investigation of Kal function, a mouse nasal explant system was employed, allowing observation of olfactory axon and GnRH cell development. Addition of Kal caused cessation of olfactory axon extension and GnRH cell migration; Kal also appeared to bind to axons or cells. The reduced outgrowth may result from an arrest of movement itself, or to increased branching at the expense of forward extension. The pausing of olfactory axons and GnRH cells, and subsequent branching, may be essential for normal development of olfactory and GnRH systems.
