Hox genes in evolution: Protein surfaces and paralog groups

Department of Developmental Biology , Stanford University, Palo Alto, California, United States
Trends in Genetics (Impact Factor: 9.92). 05/1997; 13(4):145-51. DOI: 10.1016/S0168-9525(97)01096-2
Source: PubMed


The clustered Hox genes, which encode homeodomain transcription factors, control cell fates along the anterior-posterior axis. Differences between Hox proteins cause differences between body parts. Vertebrates have 13 Hox subgroups, called paralog groups, which can be correlated with some of the insect and Amphioxus genes, and have remained distinctive for hundreds of millions of years. We identify characteristic residues that define the different paralog groups. Some paralog groups can be recognized by the homeodomain sequence alone; others only by using characteristic residues outside the homeodomain. Mapping characteristic residues onto the known homeodomain crystal structure reveals that most of the homeodomain amino acids that distinguish paralog groups are oriented away from the DNA, in positions where they might engage in protein-protein interactions.

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    • "For example, Hoxd13 directly regulates Raldh2 and affects RA production in the mouse limb (Kuss et al., 2009), and both, RA in combination with Hoxd13 expressed in the interdigit mesenchyme subsequently suppress chondrogenesis in the interdigital space (Kuss et al., 2009; Fig. 3C1). Therefore, it becomes evident that apoptosis induced digit individualization is established through complex regulatory circuits in which Hox genes control downstream molecules of limb morphogenesis that function not only on neighboring cells but also feedback and regulate in combination with the Hox proteins subsequent steps of limb formation (Goodman, 2002; Montero & Hurle, 2010; Sharkey et al., 1997; Fig. 3C1 and 2). "
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    ABSTRACT: Apoptosis is a cellular suicide program, which is on the one hand used to remove superfluous cells thereby promoting tissue or organ morphogenesis. On the other hand, the programmed killing of cells is also critical when potentially harmful cells emerge in a developing or adult organism thereby endangering survival. Due to its critical role apoptosis is tightly controlled, however so far, its regulation on the transcriptional level is less studied and understood. Hox genes, a highly conserved gene family encoding homeodomain transcription factors, have crucial roles in development. One of their prominent functions is to shape animal body plans by eliciting different developmental programs along the anterior-posterior axis. To this end, Hox proteins transcriptionally regulate numerous processes in a coordinated manner, including cell-type specification, differentiation, motility, proliferation as well as apoptosis. In this review, we will focus on how Hox proteins control organismal morphology and function by regulating the apoptotic machinery. We will first focus on well-established paradigms of Hox-apoptosis interactions and summarize how Hox transcription factors control morphological outputs and differentially shape tissues along the anterior-posterior axis by fine-tuning apoptosis in a healthy organism. We will then discuss the consequences when this interaction is disturbed and will conclude with some ideas and concepts emerging from these studies.
    Current Topics in Developmental Biology 09/2015; 114:121-58. DOI:10.1016/bs.ctdb.2015.07.014. · 4.68 Impact Factor
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    • "Hox proteins reveal that sequences are highly vari- able outside the homeodomain (reviewed in Sharkey et al., 1997), suggesting that each Hox protein, or at least each Hox paralog group, may interact with a unique set of factors. Furthermore, the number of known Hox-interacting factors is large, and ever increasing, making it unlikely that all these factors interact with Hox complexes simultaneously. "
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    ABSTRACT: Hox genes encode transcription factors with important roles during embryogenesis and tissue differentiation. Genetic analyses initially demonstrated that interfering with Hox genes has profound effects on the specification of cell identity, suggesting that Hox proteins regulate very specific sets of target genes. However, subsequent biochemical analyses revealed that Hox proteins bind DNA with relatively low affinity and specificity. Furthermore, it became clear that a given Hox protein could activate or repress transcription depending on the context. A resolution to these paradoxes presented itself with the discovery that Hox proteins do not function in isolation, but interact with other factors in complexes. The first such "cofactors" were members of the Extradenticle/Pbx and Homothorax/Meis/Prep families. However, the list of Hox-interacting proteins has continued to grow, suggesting that Hox complexes contain many more components than initially thought. Additionally, the activities of the various components and the exact mechanisms whereby they modulate the activity of the complex remain puzzling. Here we review the various proteins known to participate in Hox complexes and discuss their likely functions. We also consider that Hox complexes of different compositions may have different activities and discuss mechanisms whereby Hox complexes may be switched between active and inactive states. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
    Developmental Dynamics 01/2014; 243(1). DOI:10.1002/dvdy.23997 · 2.38 Impact Factor
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    • "functions. Specialised and common functions likely reflect the phylogeny of Hox proteins that derived through duplications from a unique or unique set of ancestral genes, leading up to 13 paraloguous groups in vertebrates (Sharkey et al., 1997). Following duplication , conservation of protein sequences likely allows for common function, while sequence divergence likely creates the frame for the acquisition of novel and distinct functions. "
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    ABSTRACT: Background: Hox genes encode transcription factors playing important role in segment specific morphogenesis along the anterior posterior axis. Most work in the Hox field aimed at understanding the basis for specialised Hox functions, while little attention was given to Hox common function. In Drosophila, genes of the Bithorax complex [Ultrabithorax (Ubx), abdominalA (abdA), and AbdominalB (AbdB)] all promote abdominal identity. While Ubx and AbdA share extensive sequence conservation, AbdB is highly divergent, questioning how it can perform similar functions as Ubx and AbdA. Results: In this study, we investigate the genetic requirement for the specification of abdominal-type denticles by Ubx, AbdA, and AbdB. The impact of ectopic expression of Hox proteins in embryos mutant for Exd as well as of Wingless or Hedgehog signaling involved in intrasegmental patterning was analyzed. Results indicated that Ubx and AbdA do not require Exd, Wg, and Hh activity for specifying abdominal-type denticles, while AbdB does. Conclusions: Our results support that distinct regulatory mechanisms underlie Ubx/AbdA- and AbdB-mediated specification of abdominal-type denticles, highlighting distinct strategies for achieving a similar biological output. This suggests that common function performed by distinct paralogue Hox proteins may also rely on newly acquired property, instead of conserved/ancestral properties.
    Developmental Dynamics 01/2014; 243(1). DOI:10.1002/dvdy.24081 · 2.38 Impact Factor
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