The role of Cdx in embryonic and adult mammalian hematopoiesis
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All blood cells orginate from a common stem cell in the bone marrow: the hematopoietic stem cell (HSC), which is characterized by two main properties: self-renewal and multipotency. Hematopoiesis is a hierarchical system with the HSC at the top. During embryogenesis, hematopoietic cells and progenitors with broader potentials are progressively generated. Mammalian hematopoietic development begins in extra-embryonic structures and continues within the embryo proper. In the conceptus, the mesoderm is patterned along the anterior-posterior (A-P) axis. The positional identity of the mesoderm on the A-P axis is regulated by Hox genes. Cdx genes, another homeobox gene family, are required for the posterior growth of axial tissues during development. Cdx genes are known to act upstream of Hox. The first evidence for a role for Cdx in hematopoiesis was established in zebrafish. Using embryoid bodies, it was shown that the Cdx genes promote embryonic hematopoiesis in the mouse by upregulating target Hox genes. Induction of Cdx4 promotes proliferation of hematopoietic progenitors. HSCs were more successfully derived from ESCs upon Cdx4 and Hoxb4 induction. Cdx gene deficiency jeopardizes embryonic hematopoiesis, with severe consequences for blood development upon Cdx2 mutations. As adult Cdx4 knockout mice only displayed minimal hematopoietic abnormalities, Cdx4 is dispensable for adult hematopoiesis. Previous studies on Cdx1 and Cdx2 mutants did not report any hematopoietic malformations either. However, it was demonstrated that overexpression of Cdx4 promotes leukemia in adult mice and that ectopic expression of Cdx2 is a key event in myeloid leukemia. The Cdx genes thus act as stimulators of hematopoietic progenitor maintenance and proliferation. Loss of function of Cdx impairs embryonic hematopoiesis, whereas gain of function in the adult bone marrow results in overproliferation of hematopoietic progenitors, which can instigate leukemia.