ABSTRACT
Type 1 and type 8 adenylate cyclases, AC1 and AC8, are membrane bound enzymes that produce cAMP in response to calcium entry and could thus control a large number of developmental processes. We provide a detailed spatiotemporal localization of these genes in the mouse brain during embryonic and postnatal life using in situ hybridization. AC1 gene expression begins early in embryonic life (before E13), and its expression is much more widespread than in adults. Transient expression of AC1 is found in the striatum, the dorsal thalamus, the trigeminal nerve nuclei, the Purkinje cells of the cerebellum, the interneurons of the hippocampus, and the retinal ganglion cells. In all these structures, the peak of AC1 gene expression occurs during early postnatal life, decreasing by P10. After P15, AC1 expression is confined to the hippocampus, the cerebral cortex, and to the granule cells of the cerebellum. AC8 gene expression also begins early in embryonic life (E12)--but in a more limited number of regions than in adults. AC8 expression is initially restricted to the epithalamus, the hypothalamus, the superior colliculus, the cerebellar anlage the proliferative zone of the rhombic lip, and the spinal cord. The expression increases and broadens during postnatal life, particularly in the thalamus and the cerebral cortex. A transient peak of AC8 expression is found in layer IV of the somatosensory cortex. Thus, AC1 and AC8 have an early developmental onset with complementary spatiotemporal distribution patterns: AC1 is most broadly distributed in embryonic life, whereas AC8 is most broadly expressed in adulthood. Transient expression of these genes designate areas that may be particularly sensitive to neural activity/calcium-modulated cAMP responses during development.
Subject(s)
Adenylyl Cyclases/metabolism , Brain/enzymology , Gene Expression Regulation, Developmental/physiology , Gene Expression/physiology , Adenylyl Cyclases/classification , Adenylyl Cyclases/genetics , Animals , Autoradiography/methods , Brain/embryology , Embryo, Mammalian , In Situ Hybridization/methods , Mice , Radioisotopes/metabolismABSTRACT
cAMP occupies a strategic position to control neuronal responses to a large variety of developmental cues. We have analyzed the role of calcium-stimulated adenylate cyclase 1 (AC1) in the development of retinal topographic maps. AC1 is expressed in retinal ganglion cells (RGCs) from embryonic day 15 to adulthood with a peak during the first postnatal week. At that time, the other calcium-stimulated AC, AC8, is expressed in the superior colliculus (SC) but not in the RGCs. In mice of the barrelless strain, which carry an inactivating mutation of the AC1 gene, calcium-stimulated AC activity is reduced by 40-60% in the SC and retina. RGC projection maps were analyzed with a variety of anterograde and retrograde tracers. After an initially normal development until postnatal day 3, retinal fibers from the ipsilateral and contralateral eye fail to segregate into eye-specific domains in the lateral geniculate nucleus and the SC. Topographic defects in the fine tuning of the retinotectal and retinogeniculate maps are also observed with abnormalities in the confinement of the retinal axon arbors in the anteroposterior and mediolateral dimensions. This is attributable to the lack of elimination of misplaced axon collaterals and to the maintenance of a transient ipsilateral projection. These results establish an essential role of AC1 in the fine patterning of the retinal map. Calcium-modulated cAMP production in the RGCs could constitute an important link between activity-dependent changes and the anatomical restructuring of the retinal terminal arbors within central targets.
