Zinc finger protein too few controls the development of monoaminergic neurons

Levkowitz, Gil; Zeller, Jörg; Sirotkin, Howard I.; French, Dorothy; Schilbach, Sarah; Hashimoto, Hisashi; Hibi, Masahiko; Talbot, William S.; Rosenthal, Arnon

doi:10.1038/nn979

Cited by 88 publications

(109 citation statements)

References 29 publications

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“…Within the brain proper, one case of such a mechanism was also reported recently: the control of the number of catecholaminergic and serotonergic neurons in the zebrafish hypothalamus by the zinc finger transcription factor Too few/Fezl (Levkowitz et al, 2003). This process is non-cell-autonomous and does not affect forebrain patterning (Levkowitz et al, 2003). The regulation of six3 cluster size that we unravel here, thus, provides a second example of such a mechanism during primary neurogenesis within the brain proper.…”

Section: Discussionsupporting

confidence: 75%

“…In this case, the signaling and relay process involved were identified: nodal signaling from the PCP promotes the production of Shh by optic stalk tissue, which in turn regulates retinal ath5 expression (Masai et al, 2000). Within the brain proper, one case of such a mechanism was also reported recently: the control of the number of catecholaminergic and serotonergic neurons in the zebrafish hypothalamus by the zinc finger transcription factor Too few/Fezl (Levkowitz et al, 2003). This process is non-cell-autonomous and does not affect forebrain patterning (Levkowitz et al, 2003).…”

Section: Discussionmentioning

confidence: 94%

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Selective control of neuronal cluster size at the forebrain/midbrain boundary by signaling from the prechordal plate

Tallafuß

Adolf

Bally‐Cuif

2003

Developmental Dynamics

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Within the vertebrate embryonic neural plate, the first neuronal clusters often differentiate at the border of patterning identities. Whether the information inherent in the intersection of patterning identities alone controls all aspects of neuronal cluster development (location, identity, and size) is unknown. Here, we focus on the cluster of the medial longitudinal fascicle (nMLF) and posterior commissure (nPC), located at the forebrain/midbrain (fore/mid) boundary, to address this issue. We first identify expression of the transcription factor Six3 as a common and distinct molecular signature of nMLF and nPC neurons in zebrafish, and we use this marker to monitor mechanisms controlling the location and number of nMLF/nPC neurons. We demonstrate that six3 expression is induced at the fore/mid boundary in pax2.1/no-isthmus and smoothened/slow muscle omitted mutants, where identities adjacent to the six3 cluster are altered; however, in these mutants, the subpopulation of six3-positive cells located within the mispatterned territory is reduced. These results show that induction of the six3 cluster is triggered by the information derived from the intersection in patterning identities alone, whereas correct cluster size depends, in a modular manner, on the identities themselves. The size of the six3 cluster is also controlled independently of neural tube patterning: we demonstrate that the prechordal plate (PCP) is impaired in mixer/bonnie and clyde mutants and that this phenotype secondarily results in an increased production of six3-positive cells at the fore/mid boundary, without correlatively affecting patterning in this area. Thus, a signaling process originating from the PCP distinguishes between neural patterning and the control of six3 cluster size at the fore/mid junction in vivo. Together, our results suggest that a combination of patterning-related and -unrelated mechanisms specifically controls the size of individual early neuronal clusters within the anterior neural plate. Developmental Dynamics 227:524 -535, 2003.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 94%

Selective control of neuronal cluster size at the forebrain/midbrain boundary by signaling from the prechordal plate

Tallafuß

Adolf

Bally‐Cuif

2003

Developmental Dynamics

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“…The zinc-finger transcriptional repressor Fezl (forebrain embryonic zinc-finger-like protein) (12)(13)(14) is expressed in cortical layers 5 and 6 (15). In zebrafish, both ectopic expression and loss-of-function analyses suggest that Fezl regulates gene expression in the ventral forebrain (14) and the development of dopaminergic and serotonergic neurons (16). Based on the expression of Fezl in the deep layers of the cerebral cortex and functional data from zebrafish, we hypothesized that Fezl regulates the specification or differentiation of layer 5 and 6 neurons during mammalian cortical development.…”

mentioning

confidence: 99%

Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex

Chen

Schaevitz

McConnell

2005

Proc. Natl. Acad. Sci. U.S.A.

333

400

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During the development of the cerebral cortex, progenitor cells produce neurons that migrate to laminar positions appropriate for their birth dates, adopt specific neuronal identities, and form appropriate local and long-distance axonal connections. Here, we report that forebrain embryonic zinc-finger-like protein (Fezl), a putative zinc-finger transcriptional repressor, is required for the differentiation of projection neurons in cortical layer 5. In Fezldeficient mice, these neurons display molecular, morphological, and axonal targeting defects. The corticospinal tract was absent in Fezl ؊/؊ mice, corticotectal and pontine projections were severely reduced, and Fezl-expressing neurons formed aberrant axonal projections. The expression of many molecular markers for deeplayer neurons was reduced or absent in the Fezl ؊/؊ cerebral cortex. Most strikingly, Ctip2, a transcription factor required for the formation of the corticospinal tract, was not expressed in the Fezl-deficient cortex. These results suggest that Fezl regulates the differentiation of layer 5 subcortical projection neurons.axon guidance ͉ cell fate ͉ corticospinal tract ͉ zinc-finger transcription factor

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“…Therefore, understanding the determination of DA phenotype and the specification of DA neuronal circuitry may provide mechanistic and therapeutic insights into these disorders. To date, only limited number of known or putative transcriptional regulators, including Pax6, Dlx, Nurr1, Lmx1a, Lmx1b, Msx1, Foggy, and Too Few (Tof͞Fez1), have been implicated in the specification of DA phenotype in vertebrates (2)(3)(4)(5)(6)(7)35). Despite this knowledge, the mechanisms leading to the early commitment of pluripotent neural stem cells to DA lineage remain elusive.…”

mentioning

confidence: 99%

“…Molecular characterizations have revealed that the too few mutant carries a point mutation that changes Cys-287 to Ser in the second of the six zinc finger motifs of the conserved zinc finger protein Fezl (Tof͞Fezl) (5). Whereas these studies establish an important role of Tof͞Fezl in DA neuron development, the mechanism by which Tof͞Fezl acts in DA neuron specification is not clear.…”

mentioning

confidence: 99%

Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl

Jeong

Einhorn

Mercurio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The development of vertebrate basal forebrain dopaminergic (DA) neurons requires the conserved zinc finger protein Too Few (Tof͞ Fezl) in zebrafish. However, how Tof͞Fezl regulates the commitment and differentiation of these DA neurons is not known. Proneural genes encoding basic helix-loop-helix transcription factors regulate the development of multiple neuronal lineages, but their involvement in vertebrate DA neuron determination is unclear. Here we show that neurogenin 1 (ngn1), a vertebrate proneural gene related to the Drosophila atonal, is expressed in and required for specification of DA progenitor cells, and when overexpressed leads to supernumerary DA neurons in the forebrain of zebrafish. Overexpression of ngn1 is also sufficient to induce tyrosine hydroxylase expression in addition to the panneuronal marker Hu in nonneural ectoderm. We further show that Tof͞Fezl is required to establish basal forebrain ngn1-expressing DA progenitor domains. These findings identify Ngn1 as a determinant of brain DA neurons and provide insights into how Tof͞Fezl regulates the development of these clinically important neuronal types.neurogenin 1 ͉ pluripotent neural stem cell ͉ neurotransmitter phenotype ͉ commitment and differentiation T he determination of neurotransmitter phenotype is an important aspect of neuronal differentiation, and in this regard, dopaminergic (DA) neurons have attracted considerable attention because of their functional and medical importance (1). Degeneration of substantia nigra DA neurons in humans is a hallmark of Parkinson's disease, and the malfunction of DA neurons in other brain regions is implicated in psychiatric disorders and neuroendocrine dysregulation. Therefore, understanding the determination of DA phenotype and the specification of DA neuronal circuitry may provide mechanistic and therapeutic insights into these disorders. To date, only limited number of known or putative transcriptional regulators, including Pax6, Dlx, Nurr1, Lmx1a, Lmx1b, Msx1, Foggy, and Too Few (Tof͞Fez1), have been implicated in the specification of DA phenotype in vertebrates (2-7, 35). Despite this knowledge, the mechanisms leading to the early commitment of pluripotent neural stem cells to DA lineage remain elusive.The earliest DA neurons in zebrafish are detected at Ϸ24 h postfertilization (hpf) in the basal forebrain (8). They express tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and dopamine transporter (DAT), a protein involved in dopamine reuptake (9). Later during development, these DA neurons have both ascending and descending projections, and are believed to be homologous to mammalian DA neurons of both the basal forebrain and midbrain (10,11).Through forward genetic analysis, an adult viable zebrafish mutant named too few (tof m808 ) has been isolated that displays selective deficits of basal forebrain DA as well as adjacent serotonergic (5HT) neurons (8). Molecular characterizations have revealed that the too few mutant carries a point mutation that changes Cys-287 t...

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Zinc finger protein too few controls the development of monoaminergic neurons

Cited by 88 publications

References 29 publications

Selective control of neuronal cluster size at the forebrain/midbrain boundary by signaling from the prechordal plate

Selective control of neuronal cluster size at the forebrain/midbrain boundary by signaling from the prechordal plate

Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex

Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl

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