Ca²⁺ signals participate in various cellular processes with spatial and temporal dynamics, Inositol 1,4,5-trisphosphate receptors (IP₃Rs)-mediated Ca²⁺ signals released from the important intracellular Ca²⁺ store endoplasmic reticulum are critical for early development, but the precise roles and underlying mechanisms of IP₃Rs in cell fate decisions remain largely unknown.

The pattern of lineage specification of embryonic stem cells (ESCs) and the underlining molecular events faithfully recapitulate the early development of the embryos. Hematopoietic and cardiac lineages are both derived from Flk1⁺ mesoderm cells, while it remains unclear how Flk1⁺ progenitor cells determine the alternative cell fate towards one of these lineages.

Recently, Dr. YANG Huangtian's team at Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences collaborating with other researchers found the previously unrecognized governing role of IP3Rs in hematopoietic and cardiac fate divergence of mouse embryonic stem cells (mESCs) via IP3Rs-Ca²⁺-calcineurin-NFATc3-Etv2 pathway. The study was published online in J Mol Cell Biol.

Deletion of IP₃Rs (IP₃Rs-tKO) reduced Flk1⁺/PDGFRa^- hematopoietic mesoderm, c-Kit⁺/CD41⁺hematopoietic progenitor cell populations and the colony-forming units activity, while it increased cardiac progenitor cells as well as cardiomyocytes.

Concomitantly, the expression of a key regulator of hematopoiesis Etv2 was reduced in IP₃R-tKO cells but rescued by the activation of Ca²⁺ signals and calcineurin or overexpression of constitutively active form of NFATc3.reversed the phenotype of IP₃R-tKO cells.

Furthermore, Etv2 was specifically targeted by NFATc3 via its evolutionarily conserved cis-element in differentiating ESCs, which was impaired by IP₃R-tKO. The activation of Ca²⁺-calcineurin-NFAT pathway

The findings provided new insights into the important role of IP3R-mediated Ca²⁺ signals in the specific lineage fate decision during early ESC differentiation and the knowledge of how IP3R-mediated Ca²⁺ directs the selection of mesoderm-derivatives.

The study was funded by National Natural Science Foundation of China, Ministry of Science and Technology of China and Chinese Academy of Sciences, etc. Professor CHEN Ju from University of California, San Diego provided Itpr1^fl/fl2^fl/fl3^fl/f mice.

Figure: A proposed model for the role of IP₃Rs-mediated Ca²⁺ signals in hematopoietic and cardiac fate commitment of mESCs. (Image by Dr. YANG Huangtian's group)