ANOSMIN-1 UNDERLYING THE X-CHROMOSOME-LINKED KALLMANN-SYNDROME IS AN ADHESION MOLECULE THAT CAN MODULATE NEURITE GROWTH IN A CELL-TYPE-SPECIFIC MANNER

Anosmin-1 is an extracellular matrix glycoprotein which underlies the X chromosome-linked form of Kallmann syndrome. This disease is charact erized by hypogonadism due to GnRH deficiency, and a defective sense o f smell related to the underdevelopment of the olfactory bulbs. This s tudy reports that anosmin-1 is an adhesion molecule for a variety of n euronal and non-neuronal cell types in vitro. We show that cell adhesi on to anosmin-1 is dependent on the presence of heparan sulfate and ch ondroitin sulfate glycosaminoglycans at the cell surface. A major cell adhesion site of anosmin-1 was identified in a 32 amino acid (32R1) s equence located within the first fibronectin-like type III repeat of t he protein. The role of anosmin-1 as a substrate for neurite growth wa s tested on either coated culture dishes or monolayers of anosmin-1-pr oducing CHO cells. In both experimental systems, anosmin-1 was shown t o be a permissive substrate for the neurite growth of different types of neurons. Mouse P5 cerebellar neurons cultured on anosmin-1 coated w ells developed long neurites; the 32R1 peptide was found to underly pa rt of this neurite growth activity. When the cerebellar neurons were c ultured on anosmin-1-producing CHO cells, neurite growth was reduced a s compared to wild-type CHO cells; in contrast, no difference was obse rved for E18 hippocanpal and P1 dorsal root ganglion neurons in the sa me experimental system. These results indicate that anosmin-1 can modu late neurite growth in a cell-type specific manner. Finally, anosmin-1 induced neurite fasciculation of P5 cerebellar neuron aggregates cult ured on anosmin-1-producing CHO cells. The pathogenesis of the olfacto ry defect in the X-linked Kallmann syndrome is discussed in the light of the present results and the recent data reporting the immunohistoch emical localisation of anosmin-1 during early embryonic development.