The discovery of conserved protein domains found in many Drosophila and mammalian developmental gene products suggests that fundamental developmental processes are conserved throughout evolution. Our understanding of development has been enhanced by the discovery of the widespread role of the homeodomain (HD). The action of HD‐containing proteins as transcriptional regulators is mediated through a helix‐turn‐helix motif which confers sequence specific DNA binding. Unexpectedly, the well conserved structural homology between the HD and the prokaryotic helix‐turn‐helix proteins contrasts with their divergent (...) types of physical interaction with DNA. A C‐terminal extension of the HD recognition helix has assumed the role that the N‐terminus of the prokaryotic helix plays for specification of DNA binding preference. However, the HD appears also capable of recognizing DNA in an alternative way and its specificity in vivo may be modified by regions outside the helix‐turn‐helix motif. We propose that this intrinsic complexity of the HD, as well as its frequent association with other DNA binding domains, explains the functional specificity achieved by genes encoding highly related HDs. (shrink)

The vertebrate Cdx genes (Cdx1 Cdx2 and Cdx4 in the mouse) encode homeodomain transcription factors related to the Drosophila caudal gene. The vertebrate Cdx gene products have been implicated in the development of the posterior embryo. In particular, loss‐ and gain‐of‐function experiments suggest that Cdx members are direct regulators of Hox genes and likely impart posterior information, in part, through this mechanism. Several signaling molecules, notably retinoic acid (RA*) and members of the Wnt (wingless) and fibroblast growth factor (FGF) (...) families, are also implicated in patterning of the posterior vertebrate embryo. Interestingly, recent work indicates that members of the Cdx family are targets of Wnt, RA and FGF signaling, suggesting that Cdx factors act to convey the activity of these signaling molecules to Hox genes. This article will briefly review Cdx expression and function, with particular emphasis on vertebrate model systems. BioEssays 25:971–980, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Hox proteins are part of the conserved superfamily of homeodomain‐containing transcription factors and play fundamental roles in shaping animal body plans in development and evolution. However, molecular mechanisms underlying their diverse and specific biological functions remain largely enigmatic. Here, we have analyzed Hox sequences from the main evolutionary branches of the Bilateria group. We have found that four classes of Hox protein signatures exist, which together provide sufficient support to explain how different Hox proteins differ in their control and (...) function. The homeodomain and its surrounding sequences accumulate nearly all signatures, constituting an extended module where most of the information distinguishing Hox proteins is concentrated. Only a small fraction of these signatures has been investigated at the functional level, but these show that approaches relying on Hox protein alterations still have a large potential for deciphering molecular mechanisms of Hox differential control. (shrink)

How the formidable diversity of forms emerges from developmental and evolutionary processes is one of the most fascinating questions in biology. The homeodomain‐containing Hox proteins were recognized early on as major actors in diversifying animal body plans. The molecular mechanisms underlying how this transcription factor family controls a large array of context‐ and cell‐specific biological functions is, however, still poorly understood. Clues to functional diversity have emerged from studies exploring how Hox protein activity is controlled through interactions with PBC (...) class proteins, also evolutionary conserved HD‐containing proteins. Recent structural data and molecular dynamic simulations add further mechanistic insights into Hox protein mode of action, suggesting that flexible folding of protein motifs allows for plastic protein interaction. As we discuss in this review, these findings define a novel type of Hox‐PBC interaction, weak and dynamic instead of strong and static, hence providing novel clues to understanding Hox transcriptional specificity and diversity. (shrink)

Hox complex genes are key developmental regulators highly conserved throughout evolution. The encoded proteins share a 60‐amino‐acid DNA‐binding motif, the homeodomain, and function as transcription factors to control axial patterning. An important question concerns the nature and function of genes acting downstream of Hox proteins. This review focuses on Drosophila, as little is known about this question in other organisms. The noticeable progress gained in the field during the past few years has significantly improved our current understanding of how (...) Hox genes control diversified morphogenesis. Here we summarise the strategies deployed to identify Hox target genes and discuss how their function contributes to pattern formation and morphogenesis. The regulation of target genes is also considered with special emphasis on the mechanisms underlying the specificity of action of Hox proteins in the whole animal. (shrink)

Despite decades of research, morphogenesis along the various body axes remains one of the major mysteries in developmental biology. A milestone in the field was the realisation that a set of closely related regulators, called Hox genes, specifies the identity of body segments along the anterior–posterior (AP) axis in most animals. Hox genes have been highly conserved throughout metazoan evolution and code for homeodomain‐containing transcription factors. Thus, they exert their function mainly through activation or repression of downstream genes. However, (...) while much is known about Hox gene structure and molecular function, only a few target genes have been identified and studied in detail. Our knowledge of Hox downstream genes is therefore far from complete and consequently Hox‐controlled morphogenesis is still poorly understood. Genome‐wide approaches have facilitated the identification of large numbers of Hox downstream genes both in Drosophila and vertebrates, and represent a crucial step towards a comprehensive understanding of how Hox proteins drive morphological diversification. In this review, we focus on the role of Hox genes in shaping segmental morphologies along the AP axis in Drosophila, discuss some of the conclusions drawn from analyses of large target gene sets and highlight methods that could be used to gain a more thorough understanding of Hox molecular function. In addition, the mechanisms of Hox target gene regulation are considered with special emphasis on recent findings and their implications for Hox protein specificity in the context of the whole organism. BioEssays 30:965–979, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The vertebrate eye lens has been used extensively as a model for developmental processes such as determination, embryonic induction, cellular differentiation, transdifferentiation and regeneration, with the crystallin genes being a prime example of developmentally controlled, tissue‐preferred gene expression. Recent studies have shown that Pax‐6, a transcription factor containing both a paired domain and homeodomain, is a key protein regulating lens determination and crystallin gene expression in the lens. The use of Pax‐6 for expression of different crystallin genes provides a (...) new link at the developmental and transcriptional level among the diverse crystallins and may lead to new insights into their evolutionary recruitment as refractive proteins. (shrink)

How transcription factors achieve their in vivo specificities is a fundamental question in biology. For the Homeotic Complex (HOM/Hox) family of homeoproteins, specificity in vivo is likely to be in part determined by subtle differences in the DNA binding properties inherent in these proteins. Some of these differences in DNA binding are due to sequence differences in the N‐terminal arms of HOM/Hox homeodomains. Evidence also exists to suggest that cofactors can modify HOM/Hox function by cooperative DNA binding interactions. The Drosophila (...) homeoprotein extradenticle (exd) is likely to be one such cofactor. In HOM/Hox proteins, both the conserved ‘YPWM’ peptide motif and the homeodomain are important for interacting with exd. Although exd provides part of the answer as to how specificity is achieved, there may be additional cofactors and mechanisms that have yet to be identified. (shrink)

We report the latest structural information on PREP1 tumor suppressor, the specific “oncogene” and “tumor suppressive” signatures of MEIS1 and PREP1, the molecular rules regulating PREP1 and MEIS1 binding to DNA, and how these can change depending on the interaction with PBX1, cell‐type, neoplastic transformation, and intracellular concentration. As both PREP1 and MEIS1 interact with PBX1 they functionally compete with each other. PREP1, PBX1, and MEIS1 TALE‐class homeodomain transcription factors act in an interdependent and integrated way in experimental tumorigenesis. (...) We also pool together the plethora of data available in human cancer databanks and connect them with the available molecular information. The emerging picture suggests that a similarly basic approach might be used to better dissect and define other oncogenes and suppressors and better understand human cancer. (shrink)

The vertebrate nervous system performs the most complex functions of any organ system. This feat is mediated by dedicated assemblies of neurons that must be precisely connected to one another and to peripheral tissues during embryonic development. Motor neurons, which innervate muscle and regulate autonomic functions, form an integral part of this neural circuitry. The first part of this review describes the remarkable progress in our understanding of motor neuron differentiation, which is arguably the best understood model of neuronal differentiation (...) to date. During development, the coordinate actions of inductive signals from adjacent non‐neural tissues initiate the differentiation of distinct motor neuron subclasses, with specific projection patterns, at stereotypical locations within the neural tube. Underlying this specialisation is the expression of specific homeodomain proteins, which act combinatorially to confer motor neurons with both their generic and subtype‐specific properties. Ensuring that specific motor neuron subtypes innervate the correct target structure, however, requires precise motor axon guidance mechanisms. The second half of this review focuses on how distinct motor neuron subtypes pursue highly specific projection patterns by responding differentially to spatially discrete attractive and repulsive molecular cues. The tight link between motor neuron specification and axon pathfinding appears to be established by the dominant role of homeodomain proteins in dictating the ways that navigating motor axons interpret the plethora of guidance cues impinging on growth cones. BioEssays 23:582–595, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The members of the Six gene family were identified as homologues of Drosophila sine oculis which is essential for compound-eye formation. The Six proteins are characterized by the Six domain and the Six-type homeodomain, both of which are essential for specific DNA binding and for cooperative interactions with Eya proteins. Mammals possess six Six genes which can be subdivided into three subclasses, and mutations of Six genes have been identified in human genetic disorders. Characterization of Six genes from various (...) animal phyla revealed the antiquity of this gene family and roles of its members in several different developmental contexts. Some members retain conserved roles as components of the Pax-Six-Eya-Dach regulatory network, which may have been established in the common ancestor of all bilaterians as a toolbox controlling cell proliferation and cell movement during embryogenesis. Gene duplications and cis-regulatory changes may have provided a basis for diverse functions of Six genes in different animal lineages. (shrink)

The emerging view of early dorso‐ventral patterning of amphibian embryos is that two opposing gradients of dorsalising and ventralising secreted factors are necessary. while several transcription factors acting upstream or downstream of the dorsalising molecules have been identified, until recently little was known about the transcriptional response to ventralising signals. Now two groups describe the identification of related homeodomain proteins, Xvent‐1 and Vox, which are able to convert dorsal cells of Xenopus embryos into more ventral ones(1,2).

Developmental coordination is vital in the temporally coordinated appearance of cell types within the precise spatial architecture of the vertebrate brain and this, combined with the rich interplay between the developing brain and its target organs, is a biological problem of monumental complexity. An example is the genesis and subsequent integration of the neuroendocrine hypothalamus and the pituitary. Two recent papers(1,2) use the developing hypothalamo‐pituitary axis in order to gather a deeper understanding of these integrative mechanisms. In addition, they show (...) that a sub‐family of homeodomain factors, the POU‐domain proteins, play a critical role in coordinating the respective ontogenies of the hypothalamus and the pituitary. (shrink)

Hox proteins are well‐known as developmental transcription factors controlling cell and tissue identity, but recent findings suggest that they are also part of the cell replication machinery. Hox‐mediated control of transcription and replication may ensure coordinated control of cell growth and differentiation, two processes that need to be tightly and precisely coordinated to allow proper organ formation and patterning. In this review we summarize the available data linking Hox proteins to the replication machinery and discuss the developmental and pathological implications (...) of this new facet of Hox protein function. (shrink)

Editor's suggested further reading in BioEssays ftz Evolution: Findings, hypotheses and speculations (response to DOI 10.1002/bies.201100019) AbstractOn the border of the homeotic function: Re‐evaluating the controversial role of cofactor‐recruiting motifs AbstractControl of DNA replication: A new facet of Hox proteins? AbstractClassification of sequence signatures: a guide to Hox protein function Abstract.