Identification of a dopaminergic enhancer indicates complexity in vertebrate dopamine neuron phenotype specification

Fujimoto, E.; Stevenson, Tamara J.; Chien, Chi Bin; Bonkowsky, Joshua L.

doi:10.1016/j.ydbio.2011.01.023

Cited by 40 publications

(62 citation statements)

References 76 publications

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“…In contrast, no stress-induced increase was observed in crh levels in the otpa m866 mutants (Figure 1G; Figure S2C). To further support this finding, we undertook a genetic approach for tissue-specific gain of function of Otpa using a transgenic zebrafish line (otp:Gal4) expressing the Gal4 protein in Otp -positive neurons (Fujimoto et al, 2011). We used the Tol2 transposon-based vectors (Kawakami et al, 2004) that efficiently integrate into the genome ensuring stable expression in 6-day-old larvae (Figure S2E).…”

Section: Resultsmentioning

confidence: 99%

“…As shown above, we injected either UAS:PAC1-short or UAS:PAC1-long constructs into the otp:Gal4 transgenic zebrafish line, expressing the Gal4 protein in the PO, which is the fish equivalent of the mammalian PVN (Fujimoto et al, 2011). Gain of function of PAC1-short resulted in a constitutive increase in crh levels, whereas overexpressing the long isoform prevented the stress- induced activation of crh transcription (Figure 6F).…”

Section: Resultsmentioning

confidence: 99%

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Homeodomain Protein Otp and Activity-Dependent Splicing Modulate Neuronal Adaptation to Stress

Amir-Zilberstein

Blechman

Sztainberg

et al. 2012

Neuron

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SUMMARY Regulation of corticotropin-releasing hormone (CRH) activity is critical for the animal’s adaptation to stressful challenges, and its dysregulation is associated with psychiatric disorders in humans. However, the molecular mechanism underlying this transcriptional response to stress is not well understood. Using various stress paradigms in mouse and zebrafish, we show that the hypothalamic transcription factor Orthopedia modulates the expression of CRH as well as the splicing factor Ataxin 2-Binding Protein-1 (A2BP1/Rbfox-1). We further show that the G protein coupled receptor PAC1, which is a known A2BP1/Rbfox-1 splicing target and an important mediator of CRH activity, is alternatively spliced in response to a stressful challenge. The generation of PAC1-hop messenger RNA isoform by alternative splicing is required for termination of CRH transcription, normal activation of the hypothalamic-pituitary-adrenal axis and adaptive anxiety-like behavior. Our study identifies an evolutionarily conserved biochemical pathway that modulates the neuronal adaptation to stress through transcriptional activation and alternative splicing.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Homeodomain Protein Otp and Activity-Dependent Splicing Modulate Neuronal Adaptation to Stress

Amir-Zilberstein

Blechman

Sztainberg

et al. 2012

Neuron

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“…Further systematic analysis of expression of transcription factors in areas of DA differentiation may lead to a more detailed understanding of transcriptional regulation in the DA systems (Li et al, 2010). A detailed understanding of transcriptional control will also involve the identification of specific response elements in the control regions of DA differentiation genes, which has only recently come to fruition with the identification of control elements of otp genes (Fujimoto et al, 2011) and th gene (Meng et al, 2008).…”

Section: Transcriptional Mechanisms Of Catecholaminergic Specificationmentioning

confidence: 99%

“…2B). Future work on axon guidance mechanisms of CA neurons will benefit from recently identified enhancers driving expression in DA neurons (Fujimoto et al, 2011). These enhancers may be used to visualize DA axons, and in combination with gain and loss of function approaches will facilitate in vivo analysis of DA axon guidance.…”

Section: Mechanisms Of Axonogenesismentioning

confidence: 99%

Dopaminergic and noradrenergic circuit development in zebrafish

Schweitzer

Löhr

Filippi

et al. 2012

Developmental Neurobiology

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Dopaminergic and noradrenergic neurons constitute some of the major far projecting systems in the vertebrate brain and spinal cord that modulate the activity of circuits controlling a broad range of behaviors. Degeneration or dysfunction of dopaminergic neurons has also been linked to a number of neurological and psychiatric disorders, including Parkinson's disease.Zebrafish (Danio rerio) have emerged over the past two decades into a major genetic vertebrate model system,and thus contributed to a better understanding of developmental mechanisms controlling dopaminergic neuron specification and axonogenesis. In this review, we want to focus on conserved and dynamic aspects of the different catecholaminergic systems, which may help to evaluate the zebrafish as a model for dopaminergic and noradrenergic cellular specification and circuit function as well as biomedical aspects of catecholamine systems.

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“…To study the role of Sim1a and Arnt2 during longitudinal HTS tract formation, we used a transgenic zebrafish line visualizing otpb-expressing neurons in the hypothalamus and their longitudinal projections towards the spinal cord by GFP (supplementary material Fig. S1) (Fujimoto et al, 2011). To analyse a potential effect of Sim1a on HTS tract formation, we injected a sim1a morpholino into otpb:gfp transgenic embryos.…”

Section: Resultsmentioning

confidence: 99%

Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism

et al. 2013

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SUMMARYPrecise spatiotemporal control of axon guidance factor expression is a prerequisite for formation of functional neuronal connections. Although Netrin/Dcc-and Robo/Slit-mediated attractive and repulsive guidance of commissural axons have been extensively studied, little is known about mechanisms controlling mediolateral positioning of longitudinal axons in vertebrates. Here, we use a genetic approach in zebrafish embryos to study pathfinding mechanisms of dopaminergic and neuroendocrine longitudinal axons projecting from the hypothalamus into hindbrain and spinal cord. The transcription factors Sim1a and Arnt2 contribute to differentiation of a defined population of dopaminergic and neuroendocrine neurons. We show that both factors also control aspects of axon guidance: Sim1a or Arnt2 depletion results in displacement of hypothalamo-spinal longitudinal axons towards the midline. This phenotype is suppressed in robo3 guidance receptor mutant embryos. In the absence of Sim1a and Arnt2, expression of the robo3 splice isoform robo3a.1 is increased in the hypothalamus, indicating negative control of robo3a.1 transcription by these factors. We further provide evidence that increased Robo3a.1 levels interfere with Robo2-mediated repulsive axon guidance. Finally, we show that the N-terminal domain unique to Robo3a.1 mediates the block of Robo2 repulsive activity. Therefore, Sim1a and Arnt2 contribute to control of lateral positioning of longitudinal hypothalamic-spinal axons by negative regulation of robo3a.1 expression, which in turn attenuates the repulsive activity of Robo2.

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Identification of a dopaminergic enhancer indicates complexity in vertebrate dopamine neuron phenotype specification

Cited by 40 publications

References 76 publications

Homeodomain Protein Otp and Activity-Dependent Splicing Modulate Neuronal Adaptation to Stress

Homeodomain Protein Otp and Activity-Dependent Splicing Modulate Neuronal Adaptation to Stress

Dopaminergic and noradrenergic circuit development in zebrafish

Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism

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