cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification.
Neuronal differentiation is accomplished through cascades of intrinsic genetic factors initiated in neuronal progenitors by external gradients of morphogens. Activity has been thought to be important only late in development, but recent evidence suggests that activity also regulates early neuronal differentiation. Activity in post-mitotic neurons before synapse formation can regulate phenotypic specification, including neurotransmitter choice, but the mechanisms are not clear. We identified a mechanism that links endogenous calcium spike activity with an intrinsic genetic pathway to specify neurotransmitter choice in neurons in the dorsal embryonic spinal cord of Xenopus tropicalis. Early activity modulated transcription of the GABAergic/glutamatergic selection gene tlx3 through a variant cAMP response element (CRE) in its promoter. The cJun transcription factor bound to this CRE site, modulated transcription and regulated neurotransmitter phenotype via its transactivation domain. Calcium signaled through cJun N-terminal phosphorylation, which integrated activity-dependent and intrinsic neurotransmitter specification. This mechanism provides a basis for early activity to regulate genetic pathways at critical decision points, switching the phenotype of developing neurons.
Marek
Kurt W
KW
Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, California, USA. kmarek@ucsd.edu
Kurtz
Lisa M
LM
Spitzer
Nicholas C
NC
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014981:Xenopus; D029867:Xenopus Proteins / Q000096:biosynthesis* / Q000235:genetics
D018398:Homeodomain Proteins; D018377:Neurotransmitter Agents; D016755:Proto-Oncogene Proteins c-jun; D029867:Xenopus Proteins; C489500:tlx3 protein, Xenopus; D002118:Calcium