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Dev Biol. February 15, 2014; 386 (2): 461-72.

Pax3 and Zic1 trigger the early neural crest gene regulatory network by the direct activation of multiple key neural crest specifiers.

Plouhinec JL , Roche DD , Pegoraro C , Figueiredo AL , Maczkowiak F , Brunet LJ , Milet C , Vert JP , Pollet N , Harland RM , Monsoro-Burq AH .

Neural crest development is orchestrated by a complex and still poorly understood gene regulatory network. Premigratory neural crest is induced at the lateral border of the neural plate by the combined action of signaling molecules and transcription factors such as AP2, Gbx2, Pax3 and Zic1. Among them, Pax3 and Zic1 are both necessary and sufficient to trigger a complete neural crest developmental program. However, their gene targets in the neural crest regulatory network remain unknown. Here, through a transcriptome analysis of frog microdissected neural border, we identified an extended gene signature for the premigratory neural crest, and we defined novel potential members of the regulatory network. This signature includes 34 novel genes, as well as 44 known genes expressed at the neural border. Using another microarray analysis which combined Pax3 and Zic1 gain-of-function and protein translation blockade, we uncovered 25 Pax3 and Zic1 direct targets within this signature. We demonstrated that the neural border specifiers Pax3 and Zic1 are direct upstream regulators of neural crest specifiers Snail1/2, Foxd3, Twist1, and Tfap2b. In addition, they may modulate the transcriptional output of multiple signaling pathways involved in neural crest development (Wnt, Retinoic Acid) through the induction of key pathway regulators (Axin2 and Cyp26c1). We also found that Pax3 could maintain its own expression through a positive autoregulatory feedback loop. These hierarchical inductions, feedback loops, and pathway modulations provide novel tools to understand the neural crest induction network.

PubMed ID: 24360906
PMC ID: PMC3962137
Article link: Dev Biol.
Grant support: GM42341 NIGMS NIH HHS , R01 GM042341 NIGMS NIH HHS , P40 OD010997 NIH HHS , 280032 European Research Council, ERC_280032 European Research Council

Genes referenced: acod1 acta1 angpt4 anos1 axin2 bnip3 btc c3 capn8 col18a1 cyp26c1 dact1 dynll1 elavl3 ets1 fgfr4 fkbp9 foxd3 fst fzd10 gbx2.1 gbx2.2 glipr2 greb1l guk1 hapln3 hoxa2 hsp90aa1.1 irf1 irx1 irx2 irx3 lmx1b.1 loc100490918 mafb meis3 mfap2 mmp28 msx1 msx2 mut myo10.2 myo1d nipal2 nrp1 olig4 pax3 pcdh8l pdgfra peli1 pfkfb4 plekhn1 pnhd prtg pts rab11fip4l rara ror2 sdhb snai1 snai2 sox10 sox9 tcf7 tenm4 tfap2a tfap2b tpbg tuba1a twist1 wls wnt1 wnt11b wnt8a xarp zfp36l2 zic1

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