A look at life from the homeodomain

Abstract

​ThisThis workshop brought together developmental biologists and oncologists for three intense days of discussions about the recent progress that has been made on the roles of homeodomain proteins in development, haematopoiesis and leukaemogenesis. The homeo-domain is a 61-amino-acid DNA-binding motif with specific sequence and structural characteristics (Gehring & Hiromi, 1986). Homeodomain proteins were initially identified in Drosophila as being responsible, when mutated, for homeotic transformations—that is, the conversion of a part of the body into the likeness of another. Since their initial discovery, the number of homeodomain proteins has increased enormously, and they comprise several different families of transcription factors. The main stars of the meeting were members of the Hox family and of the three amino-acid loop extension (TALE) families, with some other homeodomain proteins making guest appearances. TALE proteins include the PBC family (Exd in Drosophila and Pbx proteins in vertebrates) and the Hth/Meis superfamily (Hth in Drosophila, and Meis and Prep proteins in vertebrates). The link between Hox and TALE proteins is their functional interactions, which were initially revealed in flies by genetic analyses and later supported by biochemical data (Mann & Affolter, 1998; Moens & Selleri, 2006). PBC proteins have been shown to act as Hox cofactors that mainly determine Hox DNA-binding specificity and selectivity. Hth/Meis proteins interact with PBC proteins, participating in ternary complexes with Hox proteins, or modulating PBC protein stability and subcellular localization. This European Molecular Biology Organization/European School of Molecular Medicine workshop on Homeodomain Proteins, Hematopoietic Development and Leukemias took place in Riva del Garda, Italy, between 23 and 25 March 2006, and was organized by F. Blasi, ... Functional specificities and redundancies A large part of the meeting was devoted to the presentation and discussion of the consequences of the complete or partial inactivation of different TALE products in several vertebrates. These studies arrived at two main conclusions: first, TALE proteins are essential for the development of most areas of the organism; and second, they have both individual functions and a large degree of redundancy. This was clearly shown in the Pbx gene family, for which an advanced phenotypic analysis of single and compound mutants was presented. In mice, the individual contribution of each member of the family seemed to be different because, whereas the Pbx1 single mutant had a wide range of malformations, only minor or no phenotypes were obvious in Pbx2 and Pbx3 mutants. However, when a reduced Pbx2 and/or Pbx3 dosage was added to the Pbx1−/− background, strong exacerbations of the malformations were detected, as reported by L. Selleri (New York, NY, USA) and M. Cleary (Stanford, CA, USA). In particular, the cardiovascular system, the axial skeleton, the limbs and the craniofacial area were shown to be strongly affected. A.J. Waskiewicz (Edmonton, Canada) also described redundancy among Pbx genes in zebrafish, in which the functions of the Pbx2 and Pbx4 gene products seem to overlap in a range of tissues, including the hindbrain and tectum, and during early haematopoiesis. Hox gene products are known to be largely redundant, especially within paralogous groups. In the case of the Meis and Prep gene families, pleiotropic functions in patterning and differentiation processes were also described (see below); however, genetic analyses designed to evaluate the possible extent of redundancy among the different members of these gene families are still at an early stage. At the meeting, several tissues were reported to require the activity of homeodomain proteins for proper development; we highlight some of these data below.