Lamins promote trophoblast lineage-associated transcription and trophoblast giant cell development in placental organogenesis

Lamins are essential structural elements of the nuclear lamina, playing various roles in development and organogenesis. Nonetheless, the role of lamins in trophoblast development, the initial lineage to differentiate during mouse embryogenesis, is still unclear. To investigate this, scientists employed an in vitro trophoblast stem cell differentiation model in a lamin-deficient condition.

The study reveals that lamins are responsible for maintaining the expression of genes associated with trophoblast differentiation, while simultaneously suppressing genes that regulate trophoblast stem cell stemness and prevent off-lineage development.

When various combinations of lamins were deleted in mice, both lamin triple-knockout and lamin-A and -B1 (lamin-A/B1) double-knockout resulted in placental abnormalities. These abnormalities include a smaller placenta size and disrupted placental organogenesis at embryonic day E9.5. During this critical stage, lamins-A/B1 are found in trophoblast giant cells of the placenta.

In the absence of these lamins, the maturation of these giant cells is impaired in mice. Furthermore, lamin-A/B1 double knockouts exhibit smaller nuclei along with a reduction in DNA damage signaling foci, indicating that lamins play a vital role in promoting trophoblast giant cell polyploidization. These findings align with the transcriptional dysregulation observed when lamin triple knockout trophoblast stem cells were differentiated in vitro, revealing that lamin-A/B1 knockout in vivo leads to downregulation of genes related to trophoblast giant cell function and upregulation of off-lineage genes.

In summary, this research highlights the importance of lamins in placental organogenesis by ensuring polyploidization and lineage-associated transcriptional programs in trophoblast giant cells.