Project Summary/Abstract Kallmann syndrome (KS) is a condition characterized by delayed or absent puberty and an impaired sense of smell. KS results from the deficiency of early development and migration of GnRH-synthesizing neurons and olfactory nerves. Besides anosmia, there are several other associated non-reproductive features, including midline facial, dental, and digit anomalies, hearing impairment, bimanual synkinesis, and renal abnormalities. KS is clinically and genetically heterogeneous and not strictly a monogenic Mendelian disease. There are >25 different causal genes, each accounting for less than 10% of KS cases, that have been identified to date, yet the genetic basis of the vast majority of KS cases remains unknown. The KS-associated genes either act alone (monogenic) or in combination (oligogenic). However, the molecular mechanisms that modulate the oligogenic interactions are far from being elucidated since the exact roles of some susceptibility genes in the regulation of the GnRH/ olfactory nervous system are yet to be discovered. Therefore, molecular characterization of newly identified KS causative genes and their associated signaling pathways is crucial for fully determining the genetic cause of KS. The current proposal aims to understand how Neuron-Derived Neurotrophic Factor (NDNF), a novel causative gene for KS, modulates BMP signaling. If successful, the results will provide mechanistic insight underlying KS, inform genetic counseling of KS, and, in the long run, contribute to a timely diagnosis and treatment to minimize physical and psychological effects on KS patients.