Analysis of transcriptional codes for zebrafish dopaminergic neurons reveals essential functions of Arx and Isl1 in prethalamic dopaminergic neuron development

Filippi, Alida; Jainok, Chamaiphorn; Driever, Wolfgang

doi:10.1016/j.ydbio.2012.06.010

Cited by 42 publications

(48 citation statements)

References 122 publications

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“…3D). These gene expression patterns confirm previous observations in zebrafish embryos [42]–[44]. Notably, the expression pattern of p0 was markedly reduced above the otic vesicle and absent from the spinal cord in 3 dpf mct8−/− embryos (Fig.…”

Section: Resultssupporting

confidence: 91%

Altered Behavioral Performance and Live Imaging of Circuit-Specific Neural Deficiencies in a Zebrafish Model for Psychomotor Retardation

et al. 2014

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The mechanisms and treatment of psychomotor retardation, which includes motor and cognitive impairment, are indefinite. The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked psychomotor retardation characterized by delayed development, severe intellectual disability, muscle hypotonia, and spastic paraplegia, in combination with disturbed thyroid hormone (TH) parameters. AHDS has been associated with mutations in the monocarboxylate transporter 8 (mct8/slc16a2) gene, which is a TH transporter. In order to determine the pathophysiological mechanisms of AHDS, MCT8 knockout mice were intensively studied. Although these mice faithfully replicated the abnormal serum TH levels, they failed to exhibit the neurological and behavioral symptoms of AHDS patients. Here, we generated an mct8 mutant (mct8−/−) zebrafish using zinc-finger nuclease (ZFN)-mediated targeted gene editing system. The elimination of MCT8 decreased the expression levels of TH receptors; however, it did not affect the expression of other TH-related genes. Similar to human patients, mct8−/− larvae exhibited neurological and behavioral deficiencies. High-throughput behavioral assays demonstrated that mct8−/− larvae exhibited reduced locomotor activity, altered response to external light and dark transitions and an increase in sleep time. These deficiencies in behavioral performance were associated with altered expression of myelin-related genes and neuron-specific deficiencies in circuit formation. Time-lapse imaging of single-axon arbors and synapses in live mct8−/− larvae revealed a reduction in filopodia dynamics and axon branching in sensory neurons and decreased synaptic density in motor neurons. These phenotypes enable assessment of the therapeutic potential of three TH analogs that can enter the cells in the absence of MCT8. The TH analogs restored the myelin and axon outgrowth deficiencies in mct8−/− larvae. These findings suggest a mechanism by which MCT8 regulates neural circuit assembly, ultimately mediating sensory and motor control of behavioral performance. We also propose that the administration of TH analogs early during embryo development can specifically reduce neurological damage in AHDS patients.

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Section: Resultssupporting

confidence: 91%

Altered Behavioral Performance and Live Imaging of Circuit-Specific Neural Deficiencies in a Zebrafish Model for Psychomotor Retardation

et al. 2014

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“…This is consistent with our findings in the mouse, placing Arx upstream of Six3 , Isl-1 and TH expression (Figure 7). In the zebrafish studies, knockdown of either Arx or Isl-1 resulted in reduced TH staining, however, contrary to our results, neither Isl-1 or Arx expression was altered when the other was knocked down, indicating two independent pathways (43). These findings suggest that while the necessary gene expression patterns for dopaminergic fate in this region are evolutionarily conserved, the precise pathways involved in establishing these patterns differ between species.…”

Section: Discussioncontrasting

confidence: 99%

“…Using morphants of Arx and Isl-1 have indicated that while Isl-1 is required at later stages for terminal differentiation of dopamine neurons, Arx is required for earlier patterning and for the expression of Pax6a, a homolog of the mouse Pax6 (43). This is consistent with our findings in the mouse, placing Arx upstream of Six3 , Isl-1 and TH expression (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

ArxIs Required for Specification of the Zona Incerta and Reticular Nucleus of the Thalamus

Sunnen¹,

Simonet²,

Marsh³

et al. 2014

J Neuropathol Exp Neurol

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Mutations in the aristaless-related homeobox (ARX) gene result in a spectrum of structural and functional nervous system disorders including lissencephaly, movement disorders, intellectual disabilities, and epilepsy. Some patients also have symptoms indicative of hypothalamic dysfunction, however, little is known about the role of ARX in diencephalic development. To begin evaluating diencephalic defects we examined the expression of a panel of known genes and gene products that label specific diencephalic nuclei in two different Arx mutant mouse lines. Male mice engineered to have a polyalanine expansion mutation (Arx(GCG)7/Y) revealed no expression differences in any diencephalic nucleus when compared to wildtype littermates. In contrast, mice null for Arx (Arx−/Y) lost expression of specific markers of the thalamic reticular nucleus (TRN) and zona incerta (ZI), while retaining expression in other thalamic nuclei and in the hypothalamus. Tyrosine hydroxylase, a marker of the ZI’s dopaminergic A13 sub-nucleus, was among those lost, suggesting a requirement for Arx in normal TRN and ZI development, and for A13 dopaminergic fate, specifically. Since the ZI and A13 regions make connections to several hypothalamic nuclei, such mis-specification may contribute to the “hypothalamic dysfunction” observed in some patients.

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“…One transcript of interest found to be significantly increased in mutant embryos before the morphological change at st. 21 is the aristaless-related homeobox ( arx ) gene. This transcription factor is expressed early in the developing diencephalon (posterior to the retina, El-Hodiri et al, 2003; Miura et al, 1997) and is important for forebrain patterning in Xenopus , mouse and zebrafish (Filippi et al, 2012; Kitamura et al, 2002; Rodríguez-Seguel et al, 2009). The expression of the transcriptional repressor arx in rax mutant embryos begins to expand from the initial diencephalic territory into the presumptive retina at St. 19 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Xenopus mutant reveals necessity of rax for specifying the eye field which otherwise forms tissue with telencephalic and diencephalic character

Fish

Nakayama

Fisher

et al. 2014

Developmental Biology

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SUMMARY The retinal anterior homeobox (rax) gene encodes a transcription factor necessary for vertebrate eye development. rax transcription is initiated at the end of gastrulation in Xenopus, and is a key part of the regulatory network specifying anterior neural plate and retina. We describe here a Xenopus tropicalis rax mutant, the first mutant analyzed in detail from a reverse genetic screen. As in other vertebrates, this nonsense mutation results in eyeless animals, and is lethal peri-metamorphosis. Tissue normally fated to form retina in these mutants instead forms tissue with characteristics of diencephalon and telencephalon. This implies that a key role of rax, in addition to defining the eye field, is in preventing alternative forebrain identities. Our data highlight that brain and retina regions are not determined by the mid-gastrula stage but are by the neural plate stage. An RNA-Seq analysis and in situ hybridization assays for early gene expression in the mutant revealed that several key eye field transcription factors (e.g. pax6, lhx2 and six6) are not dependent on rax activity through neurulation. However, these analyses identified other genes either up- or down-regulated in mutant presumptive retinal tissue. Two neural patterning genes of particular interest that appear up-regulated in the rax mutant RNA-seq analysis are hesx1 and fezf2. These genes were not previously known to be regulated by rax. The normal function of rax is to partially repress their expression by an indirect mechanism in the presumptive retina region in wildtype embryos, thus accounting for the apparent up-regulation in the rax mutant. Knock-down experiments using antisense morpholino oligonucleotides directed against hesx1 and fezf2 show that failure to repress these two genes contributes to transformation of presumptive retinal tissue into non-retinal forebrain identities in the rax mutant.

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Analysis of transcriptional codes for zebrafish dopaminergic neurons reveals essential functions of Arx and Isl1 in prethalamic dopaminergic neuron development

Cited by 42 publications

References 122 publications

Altered Behavioral Performance and Live Imaging of Circuit-Specific Neural Deficiencies in a Zebrafish Model for Psychomotor Retardation

Altered Behavioral Performance and Live Imaging of Circuit-Specific Neural Deficiencies in a Zebrafish Model for Psychomotor Retardation

ArxIs Required for Specification of the Zona Incerta and Reticular Nucleus of the Thalamus

Xenopus mutant reveals necessity of rax for specifying the eye field which otherwise forms tissue with telencephalic and diencephalic character

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