Abstract
The evolutionarily conserved Hox family of homeodomain transcription factors plays fundamental roles in regulating cell specification along the anterior posterior axis during development of all bilaterian animals by controlling cell fate choices in a highly localized, extracellular signal and cell context dependent manner. Some studies have established downstream target genes in specific systems but their identification is insufficient to explain either the ability of Hox genes to direct homeotic transformations or the breadth of their patterning potential. To begin delineating Hox gene function in neural development we used a mouse ES cell based system that combines efficient neural differentiation with inducible Hoxb1 expression. Gene expression profiling suggested that Hoxb1 acted as both activator and repressor in the short term but predominantly as a repressor in the long run. Activated and repressed genes segregated in distinct processes suggesting that, in the context examined, Hoxb1 blocked differentiation while activating genes related to early developmental processes, wnt and cell surface receptor linked signal transduction and cell-to-cell communication. To further elucidate aspects of Hoxb1 function we used loss and gain of function approaches in the mouse and chick embryos. We show that Hoxb1 acts as an activator to establish the full expression domain of CRABPI and II in rhombomere 4 and as a repressor to restrict expression of Lhx5 and Lhx9. Thus the Hoxb1 patterning activity includes the regulation of the cellular response to retinoic acid and the delay of the expression of genes that commit cells to neural differentiation. The results of this study show that ES neural differentiation and inducible Hox gene expression can be used as a sensitive model system to systematically identify Hox novel target genes, delineate their interactions with signaling pathways in dictating cell fate and define the extent of functional overlap among different Hox genes.
Highlights
The evolutionarily conserved Hox family of homeodomain transcription factors plays fundamental roles in conferring regional identity and regulating cell specification along the anterior – posterior (AP) axis during development of all bilaterian animals [1,2]
The percentage of repressed genes increased from 55% to 73% with time suggesting that the long-term effects of Hoxb1 expression were primarily to repress genes and exclude alternative fates, consistent with Hoxb1 acting as a cell fate selector gene (Fig. 1C)
To identify Hoxb1 regulated processes we performed Gene Ontology (GO) analyses for the genes identified in the long-term induction scheme
Summary
The evolutionarily conserved Hox family of homeodomain transcription factors plays fundamental roles in conferring regional identity and regulating cell specification along the anterior – posterior (AP) axis during development of all bilaterian animals [1,2]. Evidence from diverse organisms suggests that Hox proteins act partly as high-level regulators dictating the expression levels of other regulatory proteins including themselves [6,7,8] They act partly as ground level regulators, or ‘realizators’, as initially proposed by Garcia-Bellido [9], fine-tuning very diverse processes such as cell adhesion, cell division rates, cell death and cell movement [10,11,12,13]. Considering their numbers, the scope of their functions, the context dependence of their actions and more than thirty years devoted to their study, few Hox target genes have been identified. Some studies have established direct and downstream target genes in specific systems but their identification is insufficient to explain either the ability of Hox genes to direct homeotic transformations or the diversity of their patterning potential
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
