HLX HOMEO BOX GENE IS ESSENTIAL FOR AN INDUCTIVE TISSUE INTERACTION THAT DRIVES EXPANSION OF EMBRYONIC LIVER AND GUT

The divergent murine homeo box gene Hlx is expressed in restricted hem atopoietic cell types and, during embryogenesis, prominently in viscer al mesenchyme of the developing liver, gall bladder, and gut. Targeted disruption of the gene has now established that it plays a key role i n visceral organogenesis. Embryos homozygous for the mutation died aro und embryonic day 15 with anemia and severe hypoplasia of the liver an d gut. Liver ontogeny commenced normally with formation of the liver d iverticulum and differentiation of hepatocytes, but the organ failed t o expand and reached only 3% of normal size. The apparent liver hypopl asia was not associated with a notable increase in apoptotic cells. Gu t development also began normally but the intestines failed to undergo extensive elongation and leaping and reached only a quarter of normal length. The anemia resulted from a deficiency in the fetal form of he matopoiesis, which occurs in the liver, but no intrinsic defect in Hlx (-/-) hematopoietic cells was observed in vitro, and liver-derived Hlx (-/-) hematopoietic stem cells that were transplanted to irradiated no rmal mice could fully reconstitute hematopoiesis. The impaired fetal h ematopoiesis therefore reflects insufficient support function provided by the minute liver. Hlx is normally expressed in visceral mesenchyme lying adjacent to the developing liver and gut epithelia affected by the mutation, but not in the epithelia themselves. Hence, Hlx regulate s a mesenchymal-epithelial interaction that drives a vital growth phas e in visceral organogenesis. Moreover, because mutation of Hlx blocked liver growth but not its specification, early morphogenesis, or diffe rentiation, development of this organ appears to occur by step-wise in ductive interactions under separate genetic control.