XLαs (‘extra large’ α) is a 78 kDa splice variant of the α-subunit of the heterotrimeric G protein, Gs (Nature 372 (1994) 804). Prompted by its neuroendocrine-specific tissue distribution in the adult (J. Biol. Chem. 275 (2000) 33622) and its ability to activate adenylyl cyclase (J. Biol. Chem. 275 (2000) 33633), we investigated the expression of XLαs in the developing rat nervous system using immunofluorescence. Remarkably, XLαs expression in the neural tube was found to begin at the onset of neurogenesis, being observed in a subset of mitotic neuroepithelial cells as well as in young neurons. At later developmental stages, XLαs was associated with a subset of neurons in certain regions of the nervous system such as diencephalon, midbrain, hindbrain, spinal cord and sympathetic trunk. These results suggest a role of XLαs in neuronal differentiation.