Wt1 splice isoforms bias lineage programmes before gastrulation

A team from the Max Perutz Labs at the Vienna BioCenter (Austria) has described how the gene Wt1 influences lineage-associated transcriptional programmes during formative pluripotency, the stage before gastrulation. The paper, with Martin Leeb as corresponding author, was published on 4 November 2026 in Nature Communications. doi.org Using a targeted CRISPRa screen, the authors identified Wt1 as a regulator of these programmes. doi.org

The authors frame the work around an open question in mammalian development: how transcriptional asymmetry arises in the epiblast before gastrulation. doi.org

Wt1 in formative pluripotency

According to the study, Wt1 is transiently induced during formative pluripotency both in vitro and in vivo, coinciding with emerging lineage biases. doi.org Precocious induction of Wt1 advanced cells toward post-implantation identity. doi.org

Cells deficient in Wt1 still executed naïve exit, but they showed impaired acquisition of formative and lineage-associated programmes. doi.org The authors also report that WT1 binds active regulatory elements together with OTX2, OCT4 and FOXO1. doi.org

Splice isoforms and anterior bias

The team compared Wt1 splice isoforms. KTS splice status emerged as the major determinant of divergent anterior/neuroectodermal and posterior/mesodermal transcriptional programmes in vitro. doi.org

In the E5.5 epiblast, Wt1 expression and splice composition aligned with lineage-biased states. The authors link this isoform usage to anterior bias in vivo. doi.org Isoform-dependent programmes were conserved in human pluripotent cells. doi.org

From these results the authors conclude that alternative splicing is a mechanism tuning lineage-associated transcriptional bias before gastrulation. doi.org

The data come from cell-culture experiments, an analysis of the E5.5 epiblast and human pluripotent cells. This is a fundamental study of early development, not a clinical one.

Max Perutz Labs: Wt1 splice isoforms bias lineage programmes in pluripotent cells before gastrulation

Wt1 in formative pluripotency

Splice isoforms and anterior bias

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