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Science Signaling  03 Aug 2010:
Vol. 3, Issue 133, pp. ec238
DOI: 10.1126/scisignal.3133ec238

Various aspects of neuronal development are influenced by electrical activity. Indeed, activity-dependent calcium signals prior to synapse formation can affect even such a fundamental property as neurotransmitter phenotype (and thus whether the synapse is excitatory or inhibitory). For instance, at a critical period during Xenopus spinal cord development, increased calcium spiking promotes the specification of neurons that produce the inhibitory neurotransmitters GABA and glycine, whereas decreased spiking promotes specification of neurons that produce excitatory neurotransmitters (glutamate and acetylcholine). Marek et al. injected one cell of two-cell-stage X. tropicalis embryos with mRNA encoding an inward rectifier potassium channel (Kir) to hyperpolarize neurons and thereby decrease calcium spiking unilaterally and found an increase in the area and intensity of expression of tlx3 (t-cell leukemia homeobox-3) in the dorsal spinal cord of the injected side. Manipulation of tlx3 expression with morpholino-oligonucleotides or overexpression constructs indicated that it specified glutamatergic over GABAergic fate, as it does in mouse and chick; manipulation of tlx3 combined with overexpression of Kir or of mRNA encoding sodium channels (Nav) (to increase spiking) indicated that the effects of activity on GABA or glutamate specification were upstream of tlx3. Expression of a luciferase construct driven by a conserved 384-bp region of the tlx3 promoter was modulated by coinjection of Kir or Nav, with Kir injection resulting in increased tlx3 expression and Nav injection resulting in decreased expression, and mutational analysis implicated a variant cyclic AMP response element (CRE) in this response. Electrophoretic mobility shift assays revealed that the transcription factor c-Jun bound to the CRE; moreover, a dominant-negative c-Jun mutant elicited a CRE-dependent increase in expression of the tlx3 reporter. c-Jun was present in embryonic spinal cord, and its conditional manipulation modulated neurotransmitter specification, with c-Jun overexpression promoting a GABAergic phenotype, whereas dominant-negative c-Jun promoted a glutamatergic phenotype. Although c-Jun abundance was unaffected by unilateral injection of Kir or Nav, phosphorylation of two of four residues crucial for regulation of its transactivation domain was decreased by injection of Kir and increased by injection of Nav, and expression of a c-Jun mutant in which all four residues were substituted with alanines (and thus not phosphorylatable) promoted the glutamatergic phenotype. The authors thus conclude that the calcium spiking can regulate neurotransmitter specification in this system through c-Jun–dependent modulation of tlx3 expression.

K. W. Marek, L. M. Kurtz, N. C. Spitzer, cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification. Nat. Neurosci. 13, 944–950 (2010). [PubMed]

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