Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons

Mizuguchi, Rumiko; Kriks, Sonja; Cordes, Ralf; Gossler, Achim; Ma, Qiufu; Goulding, Martyn

doi:10.1038/nn1706

Cited by 170 publications

(211 citation statements)

References 38 publications

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“…However, our results demonstrate that Tlx3 can also control expression of proneural genes, such as Mash1, Ngn1, and NeuroD. These results seem to conflict with those of a previous study in which Tlx3 was considered to be regulated by Mash1 (13)…”

Section: Discussioncontrasting

confidence: 99%

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Kondo¹,

Sheets

Zopf³

et al. 2008

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

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The T cell leukemia 3 (Tlx3) gene has been implicated in specification of glutamatergic sensory neurons in the spinal cord. In cranial sensory ganglia, Tlx3 is highly expressed in differentiating neurons during early embryogenesis. To study a role of Tlx3 during neural differentiation, mouse embryonic stem (ES) cells were transfected with a Tlx3 expression vector. ES cells stably expressing Tlx3 were grown in the presence or absence of a neural induction medium. In undifferentiated ES cells, there was no significant difference in gene expression in the presence or absence of Tlx3, even after ES cells were cultured for an extensive time period. In contrast, expression levels of Mash1, Ngn1, and NeuroD were significantly higher in Tlx3-expressing cells after neural induction for 4 days compared with those in cells expressing the control vector. At 7 days after neural induction, whereas expression of the proneural genes was down-regulated, VGLUT2, GluR2, and GluR4 were significantly increased in ES cellderived neurons expressing Tlx3. The sequential and coordinated expression of the proneural and neuronal subtype-specific genes identifies Tlx3 as a selector gene in ES cells undergoing neural differentiation. In addition, the differential effects of Tlx3 overexpression in undifferentiated ES cells compared with ES cell-derived neurons suggest that Tlx3 exerts context-dependent transcriptional signals on its downstream target genes. The context-dependent function of Tlx3 as a selector gene may be used to establish a novel strategy to conditionally generate excitatory glutamatergic neurons from ES cells to cure various types of neurodegenerative disorders.glutamatergic neurons ͉ mouse ͉ proneural genes ͉ sensory ganglia

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Section: Discussioncontrasting

confidence: 99%

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Kondo¹,

Sheets

Zopf³

et al. 2008

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

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“…Lbx1 ϩ neurons are divided into two populations, based on their nonoverlapping expression of the homeobox proteins Pax2 (DI4, DI6, and DIL A ) versus Tlx3 plus Lmx1b (DI5 and DIL B ) (Gross et al, 2002;Müller et al, 2002;Cheng et al, 2004). A set of transcription factors (TFs) acts to specify the excitatory versus the inhibitory neuron cell fates (Cheng et al, 2004(Cheng et al, , 2005Glasgow et al, 2005;Mizuguchi et al, 2006;Hori et al, 2008). Lbx1 determines a basal GABAergic inhibitory neuron cell fate (Cheng et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Lbx1 determines a basal GABAergic inhibitory neuron cell fate (Cheng et al, 2005). The homeobox proteins GSH1 and GSH2 control the expression of Tlx3, which in turn antagonizes Lbx1 to determine the glutamatergic excitatory neuron cell fate (Cheng et al, 2004(Cheng et al, , 2005Mizuguchi et al, 2006). Ptf1a acts in combination with RBPjk (recombination signal binding protein for IgJ region) to suppress Tlx3 expression and to promote GABAergic differentiation (Glasgow et al, 2005;Mizuguchi et al, 2006;Hori et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Tlx1 and Tlx3 Coordinate Specification of Dorsal Horn Pain-Modulatory Peptidergic Neurons

Xu¹,

Lopes²,

Qian³

et al. 2008

J. Neurosci.

112

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The dorsal spinal cord synthesizes a variety of neuropeptides that modulate the transmission of nociceptive sensory information. Here, we used genetic fate mapping to show that Tlx3 ϩ spinal cord neurons and their derivatives represent a heterogeneous population of neurons, marked by partially overlapping expression of a set of neuropeptide genes, including those encoding the anti-opioid peptide cholecystokinin, pronociceptive Substance P (SP), Neurokinin B, and a late wave of somatostatin. Mutations of Tlx3 and Tlx1 result in a loss of expression of these peptide genes. Brn3a, a homeobox transcription factor, the expression of which is partly dependent on Tlx3, is required specifically for the early wave of SP expression. These studies suggest that Tlx1 and Tlx3 operate high in the regulatory hierarchy that coordinates specification of dorsal horn pain-modulatory peptidergic neurons.

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“…Inhibitory and excitatory interneurons in the dorsal horn of the spinal cord require the combined actions of bHLH and homeodomain (HD) transcription factors (Gowan et al 2001;Gross et al 2002;Müller et al 2002;Cheng et al 2004Cheng et al , 2005Glasgow et al 2005;Helms et al 2005; Mizuguchi et al 2006; Wildner et al 2006). Neu-rogenesis in this CNS region is characterized by two waves: an early wave (embryonic day 10-11.5 [E10-E11.5]) that generates sensory relay and local interneurons that settle in the deep dorsal horn (dI1-dI6), and a late wave (E11.5-E13) that generates interneurons in the superficial laminae (dIL A and dIL B ) (for reviews, see Caspary and Anderson 2003;Helms and Johnson 2003).…”

mentioning

confidence: 99%

A nonclassical bHLH–Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling

Hori¹,

Cholewa-Waclaw²,

Nakada³

et al. 2008

Genes Dev.

118

144

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Neural networks are balanced by inhibitory and excitatory neuronal activity. The formation of these networks is initially generated through neuronal subtype specification controlled by transcription factors. The basic helix-loop-helix (bHLH) transcription factor Ptf1a is essential for the generation of GABAergic inhibitory neurons in the dorsal spinal cord, cerebellum, and retina. The transcription factor Rbpj is a transducer of the Notch signaling pathway that functions to maintain neural progenitor cells. Here we demonstrate Ptf1a and Rbpj interact in a complex that is required in vivo for specification of the GABAergic neurons, a function that cannot be substituted by the classical form of the bHLH heterodimer with E-protein or Notch signaling through Rbpj. We show that a mutant form of Ptf1a without the ability to bind Rbpj, while retaining its ability to interact with E-protein, is incapable of inducing GABAergic (Pax2)-and suppressing glutamatergic (Tlx3)-expressing cells in the chick and mouse neural tube. Moreover, we use an Rbpj conditional mutation to demonstrate that Rbpj function is essential for GABAergic specification, and that this function is independent of the Notch signaling pathway. Together, these findings demonstrate the requirement for a Ptf1a-Rbpj complex in controlling the balanced formation of inhibitory and excitatory neurons in the developing spinal cord, and point to a novel Notch-independent function for Rbpj in nervous system development.[Keywords: Ptf1a; Notch; cerebellum; dorsal spinal cord; neuronal specification; bHLH transcription factor] Supplemental material is available at http://www.genesdev.org.

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Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons

Cited by 170 publications

References 38 publications

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells

Tlx1 and Tlx3 Coordinate Specification of Dorsal Horn Pain-Modulatory Peptidergic Neurons

A nonclassical bHLH–Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling

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