Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut.

Abstract

The divergent murine homeo box gene Hlx is expressed in restricted hematopoietic cell types and, during embryogenesis, prominently in visceral mesenchyme of the developing liver, gall bladder, and gut. Targeted disruption of the gene has now established that it plays a key role in visceral organogenesis. Embryos homozygous for the mutation died around embryonic day 15 with anemia and severe hypoplasia of the liver and gut. Liver ontogeny commenced normally with formation of the liver diverticulum and differentiation of hepatocytes, but the organ failed to expand and reached only 3% of normal size. The apparent liver hypoplasia was not associated with a notable increase in apoptotic cells. Gut development also began normally, but the intestines failed to undergo extensive elongation and looping and reached only a quarter of normal length. The anemia resulted from a deficiency in the fetal form of hematopoiesis, 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 normal mice could fully reconstitute hematopoiesis. The impaired fetal hematopoiesis 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 regulates a mesenchymal-epithelial interaction that drives a vital growth phase in visceral organogenesis. Moreover, because mutation of H/x blocked liver growth but not its specification, early morphogenesis, or differentiation, development of this organ appears to occur by step-wise inductive interactions under separate genetic control.

Restoration of Liver Mass after Injury Requires Proliferative and Not Embryonic Transcriptional Patterns

“…Functional data exist demonstrating that many transcription factors play seminal roles in liver development, including Hlx, Prox-1, transcription factor 2 (TCF2, also HNF1␤), FoxA2 (HNF3␤) and FoxM1, genes involved in transforming growth factor ␤ signaling, SMAD (mothers against DPP homologue) 2 and SMAD3 and Jumonji, HNF6, Hes1, GATA-4, and X-box-binding protein 1 (XBP-1) (7)(8)(9)(10)(11)(12)(31)(32)(33)(34)(35). Ten of these twelve genes were not induced at least 2-fold during regeneration, whereas only two were up-regulated in a limited manner, GATA-4 1 h after regeneration, and Fox M1 48 and 72 h after regeneration (data not shown).…”

“…In contrast, many transcription factors required for liver development are more tissue-and role-specific. Homeobox factors, including Hlx and prospero-related homeobox 1, are required for normal hepatic growth and hepatoblast migration into the septum transversum mesenchyme, respectively (7,8). Bile duct formation requires hepatocyte nuclear factor-1␤ (HNF-1␤) (9).…”

Embryonic development of the liver†

“…6,15,102 Disruption in mouse embryos of the homeodomain transcription factor Hlx, whose expression is restricted to the hepatic mesenchyme, results in severe hepatic hypoplasia. 103,104 While the targets of Hlx action have yet to be defined, mouse embryos lacking either hepatocyte growth factor, which is expressed in the hepatic mesenchyme, or the hepatocyte growth factor receptor cMet, which is expressed in the hepatoblasts, also have severe liver hypoplasia. [105][106][107][108] These findings imply that the mesenchyme is a critical source of mitogenic activity that could potentially be controlled by Hlx.…”

A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice.

“…Members of the clusters specify position along axes in an embryo and limbs (1). Besides these clustered homeobox genes, certain of the unclustered and more divergent homeobox genes have been assigned roles in growth control, organogenesis, or establishment of cellular phenotypes (2)(3)(4)(5). Indeed, one of the unclustered homeobox gene, HOX11 (6)(7)(8)(9), controls the genesis of spleen (10,11).…”