A regulatory network involving Foxn4, Mash1 and delta-like 4/Notch1 generates V2a and V2b spinal interneurons from a common progenitor pool

Barrio, Marta García del; Taveira-Marques, Raquel; Muroyama, Yuko; Yuk, Dong In; Li, Shengguo; Wines-Samuelson, Mary; Shen, Jie; Smith, Hazel K.; Xiang, Mengqing; Rowitch, David H.; Richardson, William D.

doi:10.1242/dev.005868

Cited by 120 publications

(174 citation statements)

References 38 publications

(75 reference statements)

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“…Notch signaling is involved in numerous pathways of development, and previous literature has shown Notch-1 signaling favors the commitment of p2 progenitors into the V2b interneurons over V2a interneurons [25]. Expression of Gata3, a V2b interneuron marker, was significantly downregulated while Chx10 expression was upregulated after addition of 5 mM DAPT to the induction media.…”

Section: Discussionmentioning

confidence: 85%

“…1. Cells in the p2 progenitor domain express Irx3, Lhx3, and Foxn4 [19][20][21][23][24][25] and mature into three distinct interneuron classes, V2a, V2b, and V2c. V2a interneurons are excitatory, glutamatergic, and express Chx10 and Lhx3 [17,18,26], whereas V2b interneurons are inhibitory, GABAergic/glycinergic, and express Gata3 [24,[27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

“…Newly identified V2c interneurons arise from a subset of V2b interneurons, and their function in CPG networks is still unknown [33,34]. Endogenous Notch-1 signaling has been shown to influence the fate of p2 progenitors, with high Notch-1 signaling favoring differentiation into V2b interneurons over V2a interneurons [25].…”

Section: Introductionmentioning

confidence: 99%

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Generation of V2a Interneurons from Mouse Embryonic Stem Cells

Brown

Butts

McCreedy

et al. 2014

Stem Cells and Development

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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Generation of V2a Interneurons from Mouse Embryonic Stem Cells

Brown

Butts

McCreedy

et al. 2014

Stem Cells and Development

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“…This mechanism appears to be used by other CNS progenitors to generate neuronal diversity as well. For instance, during spinal cord development, Dll4 acts downstream of Foxn4 to specify the V2b inhibitory interneurons vs. the V2a excitatory interneurons (49,50), whereas Dll1 is required mainly for progenitor maintenance in the V2 domain (48).…”

Section: Dll4 Instead Of Dll1 Mediates Notch Signaling To Suppressmentioning

confidence: 99%

Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors

Luo¹,

Jin²,

Xie³

et al. 2012

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

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The generation of diverse neuronal types and subtypes from multipotent progenitors during development is crucial for assembling functional neural circuits in the adult central nervous system. During mouse retinogenesis, early retinal progenitors give rise to several cell types, including ganglion, amacrine, horizontal, cone, and rod cells. It is unknown at present how each of these fates is selected from the multiple neuronal fates available to the early progenitor. By using a combination of bioinformatic, genetic, and biochemical approaches, we investigated the mechanism by which Foxn4 selects the amacrine and horizontal cell fates from multipotential retinal progenitors. These studies indicate that Foxn4 has an intrinsic activity to suppress the alternative photoreceptor cell fates of early retinal progenitors by selectively activating Dll4-Notch signaling. Gene expression and conditional ablation analyses reveal that Dll4 is directly activated by Foxn4 via phylogenetically conserved enhancers and that Dll4 can partly mediate the Foxn4 function by serving as a major Notch ligand to expand the progenitor pool and limit photoreceptor production. Our data together define a Foxn4-mediated molecular and signaling pathway that underlies the suppression of alternative cell fates of early retinal progenitors.

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“…2H,H′). Ascl1 and Neurog factors bind to a Dll4 enhancer but only Ascl1 can activate it Dll4-Notch signaling has been demonstrated to determine the V2b versus V2a interneuron fate in the V2 domain (Del Barrio et al, 2007;Peng et al, 2007). It is therefore possible that proneural factors and Foxn4 may control the V2 fates by directly regulating Dll4 expression.…”

mentioning

confidence: 99%

Asymmetric activation of Dll4-Notch signaling by Foxn4 and proneural factors activates BMP/TGFβ signaling to specify V2b interneurons in the spinal cord

Misra

Luo

et al. 2014

Development

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During development of the ventral spinal cord, the V2 interneurons emerge from p2 progenitors and diversify into two major subtypes, V2a and V2b, that play key roles in locomotor coordination. Dll4-mediated Notch activation in a subset of p2 precursors constitutes the crucial first step towards generating neuronal diversity in this domain. The mechanism behind the asymmetric Notch activation and downstream signaling events are, however, unknown at present. We show here that the Ascl1 and Neurog basic helix-loop-helix (bHLH) proneural factors are expressed in a mosaic pattern in p2 progenitors and that Foxn4 is required for setting and maintaining this expression mosaic. By binding directly to a conserved Dll4 enhancer, Foxn4 and Ascl1 activate Dll4 expression, whereas Neurog proteins prevent this effect, thereby resulting in asymmetric activation of Dll4 expression in V2 precursors expressing different combinations of proneural and Foxn4 transcription factors. Lineage tracing using the Cre-LoxP system reveals selective expression of Dll4 in V2a precursors, whereas Dll4 expression is initially excluded from V2b precursors. We provide evidence that BMP/TGFβ signaling is activated in V2b precursors and that Dll4-mediated Notch signaling is responsible for this activation. Using a gain-of-function approach and by inhibiting BMP/TGFβ signal transduction with pathway antagonists and RNAi knockdown, we further demonstrate that BMP/TGFβ signaling is both necessary and sufficient for V2b fate specification. Our data together thus suggest that the mosaic expression of Foxn4 and proneural factors may serve as the trigger to initiate asymmetric Dll4-Notch and subsequent BMP/TGFβ signaling events required for neuronal diversity in the V2 domain.KEY WORDS: V2 interneuron, Spinal cord, Foxn4, Ascl1, bHLH proneural factor, Dll4-Notch, BMP/TGFβ, Chick, Mouse INTRODUCTIONNeuronal diversity during spinal cord (SC) development is initially generated by activities of two competing signaling pathways: sonic hedgehog (Shh) ventrally and bone morphogenetic proteins (BMPs)/Wnt dorsally (Martí et al., 1995;Ericson et al., 1997 Edlund and Jessell, 1999;Jessell, 2000;Muroyama et al., 2002). Additional pathways subsequently get involved (Sockanathan and Jessell, 1998;Novitch et al., 2003;Mizuguchi et al., 2006;Wildner et al., 2006;Del Barrio et al., 2007;Peng et al., 2007). Themed on the traditional paradigm, Hh signals are localized to the ventral SC and Gli repressor forms restrict activity in the dorsal SC (Jacob and Briscoe, 2003;Meyer and Roelink, 2003;Matise and Wang, 2011). Similarly, Wnt ligands are mostly restricted to dorsal regions, whereas inhibitors such as secreted Frizzled related proteins (sFRPs) are expressed in the ventral SC (Wodarz and Nusse, 1998;Kim et al., 2001;Kawano and Kypta, 2003). BMP/TGFβ signaling, however, does not phenocopy this model. For instance, though implicated in dorsal fate specification, expression of Tgfβ2 is observed in notochord and floor plate (García-Campmany and Martí, 2007). Additiona...

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A regulatory network involving Foxn4, Mash1 and delta-like 4/Notch1 generates V2a and V2b spinal interneurons from a common progenitor pool

Cited by 120 publications

References 38 publications

Generation of V2a Interneurons from Mouse Embryonic Stem Cells

Generation of V2a Interneurons from Mouse Embryonic Stem Cells

Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors

Asymmetric activation of Dll4-Notch signaling by Foxn4 and proneural factors activates BMP/TGFβ signaling to specify V2b interneurons in the spinal cord

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