Somatostatin and the somatostatin receptor 2 are reciprocally controlled by calcineurin during cerebellar granule cell maturation.
Activity-dependent Ca2+ influx into neurones and the subsequent changes in gene expression are thought to be important in shaping neuronal development. In this study, we investigated whether an important mediator of neuronal migration, somatostatin (Srif), alongside its receptors, is controlled in this manner in cerebellar granule cells. We show that Ca2+ influx increases the expression of somatostatin mRNA (srif), while somatostatin receptor 2 (sst2) mRNA expression is decreased. Both genes appear to be regulated independently of each other and in a calcineurin-dependent manner that does not depend on either the ERK1/2 MAP kinase or the cAMP/CREB pathway. Nonetheless, a second pathway is required to induce changes in srif and sst2 expression, since constitutively active calcineurin alone is not sufficient to induce these changes. Furthermore, calcineurin activation reciprocally regulates the expression of brain-derived neurotrophic factor, bdnf, and its receptor trkb, which have also been shown to play a role in neuronal migration. Finally, calcineurin appears to control the expression of the neuronal marker transient axonal glycoprotein 1, tag-1, thereby strongly suggesting that calcineurin activation in vivo occurs during the late stages of neuronal migration, possibly during synaptogenesis with mossy fibres. We therefore propose that calcineurin might play an important role as a switch between transcriptional programs during neuronal development.
Department of Pharmacology, Cambridge University, UK.
Dana
D
Kramer
Alessandra
A
Caruso
Ferdinando
F
Nicoletti
Armando A
AA
Genazzani
D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D019703:Calcineurin / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D004594:Electrophysiology; D005786:Gene Expression Regulation / Q000502:physiology; D006128:Growth / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism*
D011500:Protein Synthesis Inhibitors; D017481:Receptors, Somatostatin; D013004:Somatostatin; D003513:Cycloheximide; C093733:somatostatin receptor 2; D019703:Calcineurin