Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus

Abstract

V1 interneurons are inhibitory neurons that play an essential role in vertebrate locomotion. The molecular mechanisms underlying their genesis remain, however, largely undefined. Here, we show that the transcription factor Prdm12 is selectively expressed in p1 progenitors of the hindbrain and spinal cord in the frog embryo, and that a similar restricted expression profile is observed in the nerve cord of other vertebrates as well as of the cephalochordate amphioxus. Using frog, chick and mice, we analyzed the regulation of Prdm12 and found that its expression in the caudal neural tube is dependent on retinoic acid and Pax6, and that it is restricted to p1 progenitors, due to the repressive action of Dbx1 and Nkx6-1/2 expressed in the adjacent p0 and p2 domains. Functional studies in the frog, including genomewide identification of its targets by RNA-seq and ChIP-Seq, reveal that vertebrate Prdm12 proteins act as a general determinant of V1 cell fate, at least in part, by directly repressing Dbx1 and Nkx6 genes. This probably occurs by recruiting the methyltransferase G9a, an activity that is not displayed by the amphioxus Prdm12 protein. Together, these findings indicate that Prdm12 promotes V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes, and suggest that this function might have only been acquired after the split of the vertebrate and cephalochordate lineages.

A single cell transcriptome atlas of the developing zebrafish hindbrain

“…Among them, zic and her genes promote neural progenitor identity and inhibit differentation (Bae et al, 2005; Coolen et al, 2012; Nyholm et al, 2007; Scholpp et al, 2009), id genes encode negative regulators of proneural bHLH proteins (Ellis et al, 1990; Garrell and Modolell, 1990; Ling et al, 2014) and zbtb16a (plzfa) inhibits neurogenesis (Sobieszczuk et al, 2010). The following group of genes (G3) with shifting expression in pseudotime are: sox3 which has initial constant expression followed by a drop in differentiated cells; neurog1 (reviewed by Bertrand et al, 2002); prdm12b, a regulator of V1 interneuron fate decision (Thélie et al, 2015; Zannino et al, 2014); and foxp4 that is promotes detachment of differentiating cells from the neuroepithelium (Rousso et al, 2012). atoh1b and neurod4 are in the next step of the cascade (G4) together with ebf2, a factor that acts downstream of proneural genes and necessary for initiation of migration and neuronal differentiation (Garcia-Dominguez et al, 2003).…”

A Notch-regulated proliferative stem cell zone in the developing spinal cord is an ancestral vertebrate trait

“…Posterior CNS development in ascidians and amphioxus therefor differs from all vertebrates (including lampreys) in three key ways: (i) neither has a medial proliferative progenitor pool, (ii) in both lineages Notch signalling is maintained only through early development, and (iii) the expression of neuronal HLH genes is confined to scattered individual cells. To this we can add the observation that many of the genes that define vertebrate DV progenitor zones, and the pools of neurons that develop from them, are also only expressed in scattered individual cells in amphioxus, including members of the Olig , Prdm12 , Evx , Engrailed and Isl/Lhx gene families (Albuixech-Crespo et al, 2017b; Beaster-Jones et al, 2008; Ferrier et al, 2001; Holland et al, 1997; Jackman and Kimmel, 2002; Thelie et al, 2015). Furthermore, when Notch signalling is blocked in lamprey development, aspects of the resultant pattern of differentiating cells resemble what is observed in amphioxus, with scattered cells rather than clearly-defined DV zones.…”

The PAXFOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition

“…ARMS signature was composed of TFs which are not normally co-expressed in vertebrate embryos. For instance, during early/late somitogenesis in the caudal part of amniotes, LMO4 [49], MEOX1 [50], MYOD1 [51], PITX2 [52] label embryonic muscle cells, FOXF1 [53] is in the sclerotome and PAX2 [54], PRDM12 [55], TFAP2 mark neurons of the peripheral and/or central nervous system. This suggests that ARMS cells are not simply undifferentiated muscle cells, but rather as cells with their own transcriptional status.…”