The differentiation and movement of presomitic mesoderm progenitor cells are controlled by Mesogenin 1

Abstract

SUMMARYSomites are formed from the presomitic mesoderm (PSM) and give rise to the axial skeleton and skeletal muscles. The PSM is dynamic; somites are generated at the anterior end, while the posterior end is continually renewed with new cells entering from the tailbud progenitor region. Which genes control the conversion of tailbud progenitors into PSM and how is this process coordinated with cell movement? Using loss-and gain-of-function experiments and heat-shock transgenics we show in zebrafish that the transcription factor Mesogenin 1 (Msgn1), acting with Spadetail (Spt), has a central role. Msgn1 allows progression of the PSM differentiation program by switching off the progenitor maintenance genes ntl, wnt3a, wnt8 and fgf8 in the future PSM cells as they exit from the tailbud, and subsequently induces expression of PSM markers such as tbx24. msgn1 is itself positively regulated by Ntl/Wnt/Fgf, creating a negative-feedback loop that might be crucial to regulate homeostasis of the progenitor population until somitogenesis ends. Msgn1 drives not only the changes in gene expression in the nascent PSM cells but also the movements by which they stream out of the tailbud into the PSM. Loss of Msgn1 reduces the flux of cells out of the tailbud, producing smaller somites and an enlarged tailbud, and, by delaying exhaustion of the progenitor population, results in supernumerary tail somites. Through its combined effects on gene expression and cell movement, Msgn1 (with Spt) plays a key role both in genesis of the paraxial mesoderm and in maintenance of the progenitor population from which it derives.

FGF and canonical Wnt signaling cooperate to induce paraxial mesoderm from tailbud neuromesodermal progenitors through regulation of a two-step epithelial to mesenchymal transition

“…3I-L′, white arrowheads). The regulation of msgn1 in the tailbud by FGF signaling has also been demonstrated previously (Fior et al, 2012). Gain of FGF function had the opposite effect, again most notably in the posteriormost domain ( Fig.…”

“…Homozygous tbx16 mutants exhibit greatly expanded ntla expression in the tailbud (Fior et al, 2012;Yabe and Takada, 2012). During tailbud mesoderm induction from NMPs, future mesodermal cells undergo a two-step EMT .…”

“…In the second step, non-directional mesenchyme acquires directional movement and cells exit the tailbud. The second step is dependent on Tbx16 and Msgn1 function; they promote exit from the tailbud as well as repression of ntla expression (Bouldin et al, 2015;Fior et al, 2012;Manning and Kimelman, 2015;Row et al, 2011). Based on the similarity in phenotype, we reasoned that loss of FGF signaling might specifically affect the ability to complete the second step of the EMT process.…”

The zebrafish tailbud contains two independent populations of midline progenitor cells that maintain long-term germ layer plasticity and differentiate based on local signaling cues

“…For example, we showed that msgn1 must be excluded from MPCs in order for mesodermal descendants to join the notochord rather than somites. Expression of msgn1 in cells that will form somites involves positive inputs from T-box transcription factors, canonical Wnt signaling, and FGF signaling, which may only occur at the correct levels in the region of the PWPCs (Fior et al, 2012;Wittler et al, 2007;Yabe and Takada, 2012). Alternatively, the unique signaling environment of the MPCs can turn on the specific expression of transcriptional repressors such as flh, which may inhibit msgn1 expression, similar to its normal role in inhibiting tbx16 (also known as spadetail) expression (Amacher and Kimmel, 1998).…”

“…7B,B′). Embryos also appear shorter than their wild-type siblings, which is likely to be due to the ability of msgn1 to promote the differentiation rather than maintenance of PWPCs, which prematurely exhausts this progenitor pool (Fior et al, 2012;Yabe and Takada, 2012). When msgn1 is induced throughout the embryo at the end of gastrulation (bud stage), the notochord ends abruptly and there is a transition to midline somite formation (Fig.…”