PT  - JOURNAL ARTICLE
AU  - Frum, Tristan
AU  - Ralston, Amy
TI  - HIPPO signaling provides a fail-safe for resolving embryonic cell fate conflicts during establishment of pluripotency in vivo
AID  - 10.1101/316539
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 316539
4099  - http://biorxiv.org/content/early/2018/05/08/316539.short
4100  - http://biorxiv.org/content/early/2018/05/08/316539.full
AB  - In mammals, the first few days of development entail segregation of pluripotent and extraembryonic trophectoderm cells. The challenge for the embryo at this time is to override cell plasticity to ensure that cells adopt distinct fates. Here, we identify novel mechanisms restricting expression of Sox2 and Cdx2 to mutually exclusive domains. We show that Sox2 is repressed in the trophectoderm downstream of ROCK1/2 and HIPPO pathway LATS1/2 kinases. LATS1/2 kinases are thought to antagonize YAP1 and WWTR1, the transcriptional partners of TEAD4. However, the combined loss of Yap1; Wwtr1 has not been reported. Using female germ line deletion and null alleles, we show that YAP1/WWTR1/TEAD4 simultaneously antagonize Sox2 and promote Cdx2 expression in trophectoderm. However, Cdx2 is less sensitive to Yap1 and Wwtr1 dosage, which can lead cells to aberrantly coexpress CDX2 and SOX2, reminiscent of conflicted cell fate. We show that HIPPO resolves cell fate conflicts by elevating Sox2 expression and driving cells to the inner cell mass, but Sox2 is not required for HIPPO-mediated cell repositioning. Rather, HIPPO signaling represses cell polarity components PAR and aPKC, facilitating cell internalization upstream of Sox2. We propose that HIPPO engages in negative feedback and PAR-aPKC providing a fail-safe to ensure lineage segregation.