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Hop Is an Unusual Homeobox Gene That Modulates Cardiac Development

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Hop Is an Unusual Homeobox Gene That Modulates Cardiac Development Cell, Vol. 110, 713–723, September 20, 2002, Copyright 2002 by Cell Press Hop Is an Unusual Homeobox Gene that Modulates Cardiac Development Fabian Chen,1 Hyun Kook,1 Rita Milewski,1 tion and are arranged in the genome in the order in Aaron D. Gitler,1,2 Min Min Lu,1 Jun Li,1 which they are expressed along the axis of the embryo. Ronniel Nazarian,1 Robert Schnepp,1 The “Hox code” represents an important paradigm for Kuangyu Jen,1 Christine Biben,3 Greg Runke,2 the definition of positional identity during embryogene- Joel P. Mackay,5 Jiri Novotny,3 sis in which the specific pattern of overlapping Hox gene Robert J. Schwartz,6 Richard P. Harvey,3,4 expression defines cellular identity. A plethora of non- Mary C. Mullins,2 and Jonathan A. Epstein1,2,7 clustered Hox genes have been identified that are scat- 1Department of Medicine tered throughout the genome and play additional roles 2 Department of Cell and Developmental Biology in cell fate specification in all organs and tissues of the University of Pennsylvania Health System body. Philadelphia, Pennsylvania 19104 Hox genes are defined by the presence of a 60 amino 3 The Victor Chang Cardiac Research Institute acid domain that mediates DNA binding. This domain Darlinghurst, NSW 2010 has been analyzed by NMR spectroscopy and X-ray Australia crystallography either free or in association with DNA 4 Faculties of Medicine and Life Sciences (Kissinger et al., 1990; Qian et al., 1989; Wolberger et University of New South Wales al., 1991). The 60 amino acid homeodomain is capable Kensington, NSW 2051 of adopting a fixed structure in solution composed of Australia three ␣ helices in which the second and third helices 5 School of Molecular and Microbial Biosciences form a helix-turn-helix motif. The third helix sits in the University of Sydney major groove of DNA and makes critical DNA contacts. NSW 2006 Within this third ␣ helix, several amino acids that make Australia direct contact with DNA are conserved amongst all 6 Department of Cell Biology known homeodomains. Other residues vary only slightly Baylor College of Medicine and define subclasses of Hox genes. For instance, ho- Houston, Texas 77030 meodomains of the goosecoid class contain a lysine at position 9 of the third helix, while those of the paired class contain a serine at this position (Duboule, 1994). Summary Hox proteins are thought to act by modulating tran- scription, and all known Hox gene products contain do- Hop is a small, divergent homeodomain protein that mains in addition to the homeodomain that are capable lacks certain conserved residues required for DNA of activating or repressing transcription, mediating pro- binding. Hop gene expression initiates early in cardio- tein-protein interactions or binding to DNA. For instance, genesis and continues in cardiomyocytes throughout in the developing heart, Nkx2-5 encodes a homeodo- embryonic and postnatal development. Genetic and main protein that includes amino-terminal and carboxy- biochemical data indicate that Hop functions directly terminal transcriptional activation domains in addition downstream of Nkx2-5. Inactivation of Hop in mice to the homeodomain (Chen and Schwartz, 1995; Komuro and Izumo, 1993; Lyons et al., 1995; Ranganayakulu et by homologous recombination results in a partially al., 1998). Nkx2-5 is homologous to the Drosophila gene penetrant embryonic lethal phenotype with severe de- tinman that is required for heart formation in the fly velopmental cardiac defects involving the myocar- (Komuro and Izumo, 1993). In vertebrates, multiple re- dium. Inhibition of Hop activity in zebrafish embryos lated Nkx2 homeobox genes are expressed in the heart likewise disrupts cardiac development and results in and probably serve redundant functions (Harvey, 1996). severely impaired cardiac function. Hop physically in- In Xenopus embryos, injection of dominant-negative teracts with serum response factor (SRF) and inhibits forms of Nkx2-5/Nkx2-3 prevent cardiac development activation of SRF-dependent transcription by inhib- (Fu et al., 1998). iting SRF binding to DNA. Hop encodes an unusual Nkx2-5 acts synergistically with other transcription homeodomain protein that modulates SRF-dependent factors expressed in the developing heart to activate cardiac-specific gene expression and cardiac devel- expression of cardiac-specific genes. In particular, opment. Nkx2-5, Gata4, and serum response factor (SRF) func- tion together by binding to adjacent sites within the Introduction promoter/enhancer region of cardiac genes (Chen et al., 1996; Chen and Schwartz, 1996; Durocher et al., 1997). One of the landmark discoveries in developmental biol- This particular constellation of binding sites is found ogy was the identification of clustered homeobox or in the upstream genomic regions of some, but not all, Hox genes that encode transcription factors required developmentally regulated cardiac genes. Recently, a for patterning the embryo along the anterior-posterior cardiac-specific transcription cofactor named myocar- axis (reviewed in Duboule, 1994). These clustered Hox din was identified that contains a homeobox-like subdo- genes are conserved across millions of years of evolu- main and binds to SRF, effecting potent transcriptional activation (Wang et al., 2001). Hence, multiple cardiac- 7 Correspondence: [email protected] specific gene regulatory networks converge on SRF to Cell 714 Figure 1. Sequence and Expression of Anal- ysis of Hop (A) Mouse and human amino acid sequence for Hop. A comparison is made with Xenopus Goosecoid, human PAX6, and a consensus homeodomain sequence (Duboule, 1994). Conserved amino acid residues are shown in red. Amino acid residues conserved in all homeodomain are shown in blue. Hop has a lysine at amino acid position 52 (*), which is typical of the Goosecoid protein. Hop also has a glutamine at position 53 (†) and a leu- cine at 55 (†), which differ from the highly conserved asparagine and arginine, respec- tively found in all other homeodomains. (B) Whole-mount in situ at E9.5 revealing ex- pression in the branchial arches (ba) and heart (ht). (Signal in the hindbrain is artifactual due to probe trapping.) (C) Whole-mount in situ reveals expression of Hop in the heart at E10.5 (left) and in the heart and neural tube (nt) at E12.5 (right). The heads have been removed to improve visual- ization of the heart. (D) Posterior view at E12.5 indicating expres- sion in the neural tube. (E) Radioactive in situ hybridization of trans- verse section at E12.5 reveals strong Hop expression in all four cardiac chambers (ht) and in the ventricular zone of the neural tube (nt). (F) Northern blot of mouse Hop demonstrating a 1.2 kb mRNA transcript present in E12.5 heart and not in the embryo with the heart removed. Adult mouse heart, brain, intestine, and spleen express Hop mRNA. mediate cardiac gene transcription during development ing frame with a 60 amino acid motif homologous to and disease. Hox gene products. At the amino acid sequence level, In this report, we describe and characterize an un- Hop is most closely related to homeodomain proteins %57ف identity and %40ف usual type of homeodomain protein that functions dur- Pax6 and goosecoid, with ing cardiac development called Hop (homeodomain only similarity evident within the homeodomain-like domain protein, previously referred to as Toto and identified (Figure 1A). Optimal alignment strategies suggest that independently by others as Cameo; Shin et al., 2002 [this Hop has a single amino acid insertion near the end issue of Cell]). Hop is coexpressed with and functions of the predicted first ␣ helix when compared to other downstream of the mammalian tinman homolog Nkx2-5. homeodomain proteins. To model the Hop protein Hop is the smallest known homeodomain protein. It is against other known protein structures, we subjected composed of a divergent homeodomain that is incapa- the 73 amino acid Hop sequence to protein threading ble of sequence-specific DNA binding. Instead, Hop calculations using the ProCeryon algorithm (Sippl and functions by interacting with SRF to inhibit DNA binding. Weitckus, 1992; Jones et al., 1992). Results indicated This interaction results in decreased transcription of that some 6 homeodomain structures from species as SRF-dependent cardiac-restricted genes. Genetic inac- diverse as fruitfly and man scored higher than any other tivation of Hop in mice results in a partially penetrant protein in the PDB, making it highly probable that Hop phenotype of embryonic heart failure and lethality, while belongs to the homeodomain superfamily. The highest morpholino antisense oligonucleotide inactivation of scoring homeodomain folds were those of Drosophila Hop in zebrafish results in impaired cardiac contractility paired and engrailed, and human PBX1 and HOX-B1, and function. Our results identify an atypical homeodo- showing 19%–28% residues both aligned in sequence main protein and describe an unusual function for this and structurally superimposed. Least squares (best fit) conserved structural motif in heart development. superimpositions showed these 4 homeodomains to be highly similar in their detailed structures (average root- Results mean-square error of 1.4 A˚ ). This group of homeodo- mains therefore provides an excellent structural tem- We identified mouse Hop in an expressed sequence tag plate for the Hop fold. (EST) database search for transcripts encoding proteins Like goosecoid, Hop has a Lys at position 52 (see related to paired-type homeodomains expressed in the numbering in Figure 1A; this position in Hop corre- heart. Further analysis of EST databases revealed a hu- sponds to position 50 of the goosecoid homeodomain). man homolog of Hop (designated HOP), encoding a This amino acid has been identified as an important protein with 92% identity to the mouse sequence (Figure contributor to DNA binding specificity of most homeo- 1A). Homologs were also present in rat, cow, pig, chick, domains (Treisman et al., 1989). Furthermore, Hop con- Xenopus, and zebrafish, but we failed to identify C.
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