How do ci-regulatory differences, across mouse subspecies and over evolutionary timescales, shape cell-type specification and maturation during corticogenesis? In this issue of Developmental Cell, Medina-Cano et al. establish a scalable mouse organoid platform that recapitulates developmental dynamics and enables mapping of allele-specific expression, linking cis-regulatory variation with neurodevelopmental mechanisms and disease-associated genetics.
The mechanisms by which basement membranes (BMs) adjust their mechanical properties to meet the biophysical needs of organs remain unclear. In this issue of Developmental Cell, Soh et al. establish the Caenorhabditis spermatheca as a model for repeated stretching and relaxation of the BM during the continuous ovulation process and demonstrate high, fibulin-dependent elasticity.
KRAS mutations drive pancreatic ductal adenocarcinoma (PDAC). In this issue of Developmental Cell, Salomó Coll et al.1 reveal that KRAS suppresses endoplasmic reticulum (ER)-phagy in pancreatic acinar cells by inhibiting CCPG1 transcription. Impaired ER-phagy triggers protein aggregation, inflammation, and acinar-to-ductal metaplasia, promoting tumorigenesis. These findings highlight selective autophagy's role in cancer, with possible therapeutic implications.
Lineage specification requires accurate interpretation of multiple signaling cues. However, how combinatorial signaling histories influence fate outcomes remains unclear. We combined single-cell transcriptomics, live-cell imaging, and mathematical modeling to explore how activin and bone morphogenetic protein 4 (BMP4) guide fate specification during human gastrulation. We see that these signals interact both synergistically and antagonistically to drive fate decisions. We find that definitive endoderm arises from lineage convergence: a direct route from pluripotency and an indirect route via a mesoderm progenitor state. Cells pass through temporal windows of signaling competency, and the relative concentration of activin and BMP4 dictates the trajectory choice. The efficiency between routes is underpinned by a dual role of BMP4 in inducing mesoderm genes while promoting pluripotency exit. This work underscores that the combination of signals a cell is exposed to not only directs its final fate but also the developmental route taken, suggesting lineage convergence enhances robustness in fate specification.

