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Retinoic acid (RA) is a well‐established inducer of  Hox  genes during development of neurectoderm, however effects of RA on  Hox  expression are poorly defined in mesoderm and not defined in the hematopoietic compartment. Both  Ho x genes and retinoid signaling have been suggested to modulate hematopoietic stem cell (HSC) self‐renewal, supporting the notion that RA signaling might drive HSC self‐renewal through  Hox  gene induction. Here, we investigate this possibility by comprehensively evaluating  Hox  gene expression using mouse embryonic stem cells differentiated in vitro. In unspecified mesoderm, we find that RA coordinately upregulates anterior 3′  Hox  genes from clusters A, B, and C, and downregulates posterior 5′  Hox  genes from clusters A–D. However, hematopoietic development of mesoderm was inhibited by RA, and we find further that retinoids are entirely dispensable for hematopoiesis in vitro. More surprisingly, in fully specified hematopoietic progenitors,  Hox  genes are refractory to regulation by RA, although other RA targets are normally regulated. Pulses of RA exposure demonstrate that the  Hox  complexes are decoupled from RA regulation progressively in lateral plate mesoderm as it undergoes hematopoietic specification. Thus,  Hox  genes are targets of the RA pathway only in selected cell types, and are clearly not regulated by RA in the earliest hematopoietic progenitors. We propose that the developmental uncoupling of the Hox complexes protects the Hox code from potential RA signaling centers as HSCs migrate or circulate during development. S TEM  C ELLS  2010; 28:1518–1529.

The Retinoid Signaling Pathway Inhibits Hematopoiesis and Uncouples from the Hox Genes During Hematopoietic Development