@article {136, title = {Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior.}, journal = {Neuron}, volume = {67}, year = {2010}, month = {2010 Jul 29}, pages = {321-34}, abstract = {

Genetic programs, environmental factors, and electrical activity interact to drive the maturation of the brain. Although the cascade of transcription factors that leads to specification of the serotonergic phenotype has been well characterized, its interactions with electrical activity are not known. Here we show that spontaneous calcium spike activity in the hindbrain of developing Xenopus laevis larvae modulates the specification of serotonergic neurons via regulation of expression of the Lmx1b transcription factor. Activity acts downstream of Nkx2.2 but upstream of Lmx1b, leading to regulation of the serotonergic phenotype. Using global manipulation of activity and targeted alteration of Lmx1b expression, we also demonstrate that changes in the number of serotonergic neurons change larval swimming behavior. The results link activity-dependent regulation of a transcription factor to transmitter specification and altered behavior.

}, keywords = {Action Potentials, Animals, Behavior, Animal, Bromodeoxyuridine, Calcium, Electroporation, Embryo, Nonmammalian, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Homeodomain Proteins, Membrane Potentials, Neurons, Otx Transcription Factors, Potassium Channels, Inwardly Rectifying, Raphe Nuclei, RNA, Messenger, Serotonin, Sodium Channels, Statistics, Nonparametric, Swimming, Transcription Factors, Tryptophan Hydroxylase, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2010.06.006}, author = {Demarque, Micha{\"e}l and Spitzer, Nicholas C} } @article {135, title = {cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification.}, journal = {Nat Neurosci}, volume = {13}, year = {2010}, month = {2010 Aug}, pages = {944-50}, abstract = {

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.

}, keywords = {Animals, Base Sequence, Calcium, Calcium Signaling, Electrophoretic Mobility Shift Assay, Gene Expression, Gene Expression Regulation, Developmental, Homeodomain Proteins, Immunohistochemistry, In Situ Hybridization, Molecular Sequence Data, Neurogenesis, Neurons, Neurotransmitter Agents, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Xenopus, Xenopus Proteins}, issn = {1546-1726}, doi = {10.1038/nn.2582}, author = {Marek, Kurt W and Kurtz, Lisa M and Spitzer, Nicholas C} } @article {132, title = {Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification.}, journal = {J Neurosci}, volume = {28}, year = {2008}, month = {2008 Apr 30}, pages = {4777-84}, abstract = {

Neurotransmitter signaling in the mature nervous system is well understood, but the functions of transmitters in the immature nervous system are less clear. Although transmitters released during embryogenesis regulate neuronal proliferation and migration, little is known about their role in regulating early neuronal differentiation. Here, we show that GABA and glutamate drive calcium-dependent embryonic electrical activity that regulates transmitter specification. The number of neurons expressing different transmitters changes when GABA or glutamate signaling is blocked chronically, either using morpholinos to knock down transmitter-synthetic enzymes or applying pharmacological receptor antagonists during a sensitive period of development. We find that calcium spikes are triggered by metabotropic GABA and glutamate receptors, which engage protein kinases A and C. The results reveal a novel role for embryonically expressed neurotransmitters.

}, keywords = {Animals, Antigens, CD57, Calcium, Choline O-Acetyltransferase, Embryo, Nonmammalian, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Glutamate Decarboxylase, Glutamic Acid, Health Services Research, Larva, Morpholines, Neurons, Phosphoserine, Receptors, GABA, Receptors, Glutamate, Synapses, Vesicular Glutamate Transport Proteins, Xenopus}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4873-07.2008}, author = {Root, Cory M and Vel{\'a}zquez-Ulloa, Norma A and Monsalve, Gabriela C and Minakova, Elena and Spitzer, Nicholas C} } @article {133, title = {Illumination controls differentiation of dopamine neurons regulating behaviour.}, journal = {Nature}, volume = {456}, year = {2008}, month = {2008 Nov 13}, pages = {195-201}, abstract = {

Specification of the appropriate neurotransmitter is a crucial step in neuronal differentiation because it enables signalling among populations of neurons. Experimental manipulations demonstrate that both autonomous and activity-dependent genetic programs contribute to this process during development, but whether natural environmental stimuli specify transmitter expression in a neuronal population is unknown. We investigated neurons of the ventral suprachiasmatic nucleus that regulate neuroendocrine pituitary function in response to light in teleosts, amphibia and primates. Here we show that altering light exposure, which changes the sensory input to the circuit controlling adaptation of skin pigmentation to background, changes the number of neurons expressing dopamine in larvae of the amphibian Xenopus laevis in a circuit-specific and activity-dependent manner. Neurons newly expressing dopamine then regulate changes in camouflage colouration in response to illumination. Thus, physiological activity alters the numbers of behaviourally relevant amine-transmitter-expressing neurons in the brain at postembryonic stages of development. The results may be pertinent to changes in cognitive states that are regulated by biogenic amines.

}, keywords = {Animals, Behavior, Animal, Cell Count, Cell Differentiation, Chelating Agents, Dopamine, Egtazic Acid, Gene Expression Regulation, Developmental, Larva, Light, Lighting, Melanotrophs, Neurons, Neuropeptide Y, Photic Stimulation, Skin Pigmentation, Sodium Channel Blockers, Suprachiasmatic Nucleus, Tetrodotoxin, Xenopus laevis}, issn = {1476-4687}, doi = {10.1038/nature07569}, author = {Dulcis, Davide and Spitzer, Nicholas C} } @article {143, title = {Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila.}, journal = {Nat Neurosci}, volume = {10}, year = {2007}, month = {2007 Sep}, pages = {1160-7}, abstract = {

Epidermal growth factor receptor (EGFR) signaling in the mammalian hypothalamus is important in the circadian regulation of activity. We have examined the role of this pathway in the regulation of sleep in Drosophila melanogaster. Our results demonstrate that rhomboid (Rho)- and Star-mediated activation of EGFR and ERK signaling increases sleep in a dose-dependent manner, and that blockade of rhomboid (rho) expression in the nervous system decreases sleep. The requirement of rho for sleep localized to the pars intercerebralis, a part of the fly brain that is developmentally and functionally analogous to the hypothalamus in vertebrates. These results suggest that sleep and its regulation by EGFR signaling may be ancestral to insects and mammals.

}, keywords = {Analysis of Variance, Animals, Animals, Genetically Modified, Behavior, Animal, Drosophila, Drosophila Proteins, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Developmental, Membrane Proteins, Motor Activity, Receptor, Epidermal Growth Factor, Signal Transduction, Sleep}, issn = {1097-6256}, doi = {10.1038/nn1957}, author = {Foltenyi, Krisztina and Greenspan, Ralph J and Newport, John W} } @article {131, title = {Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction.}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, year = {2007}, month = {2007 Jan 2}, pages = {335-40}, abstract = {

Signaling in the nervous system requires matching of neurotransmitter receptors with cognate neurotransmitters at synapses. The vertebrate neuromuscular junction is the best studied cholinergic synapse, but the mechanisms by which acetylcholine is matched with acetylcholine receptors are not fully understood. Because alterations in neuronal calcium spike activity alter transmitter specification in embryonic spinal neurons, we hypothesized that receptor expression in postsynaptic cells follows changes in transmitter expression to achieve this specific match. We find that embryonic vertebrate striated muscle cells normally express receptors for glutamate, GABA, and glycine as well as for acetylcholine. As maturation progresses, acetylcholine receptor expression prevails. Receptor selection is altered when early neuronal calcium-dependent activity is perturbed, and remaining receptor populations parallel changes in transmitter phenotype. In these cases, glutamatergic, GABAergic, and glycinergic synaptic currents are recorded from muscle cells, demonstrating that activity regulates matching of transmitters and their receptors in the assembly of functional synapses.

}, keywords = {Animals, Calcium, Gene Expression Regulation, Developmental, Muscle, Skeletal, Neuromuscular Junction, Neurotransmitter Agents, Receptors, Neurotransmitter, Spinal Cord, Synapses, Xenopus}, issn = {0027-8424}, doi = {10.1073/pnas.0607450104}, author = {Borodinsky, Laura N and Spitzer, Nicholas C} }