Morphological change caused by loss of the taxon-specific polyalanine tract in Hoxd-13.

Sequence comparison of Hoxd-13 among vertebrates revealed the presence of taxon-specific polyalanine tracts in amniotes. To investigate their function at the organismal level, we replaced the wild-type Hoxd-13 gene with one lacking the 15-residue polyalanine tract by using homologous recombination. Sesamoid bone formation in knock-in mice was different from that in the wild type; this was observed not only in the homozygotes but also in the heterozygotes. The present study provides the first direct evidence that taxon-specific homopolymeric amino acid repeats are involved in phenotypic diversification at the organismal level.

[1]  F. Goodman,et al.  Limb malformations and the human HOX genes. , 2002, American journal of medical genetics.

[2]  K. Jeang,et al.  Glutamine-rich Domains Activate Transcription in YeastSaccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.

[3]  H. Hoenecke,et al.  The sesamoids of the metacarpo-phalangeal joint of the thumb: an anatomical and clinical study. , 1989, Journal of hand surgery.

[4]  S. Rusconi,et al.  Transcriptional activation modulated by homopolymeric glutamine and proline stretches. , 1994, Science.

[5]  B. Brais,et al.  Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains. , 2003, Human molecular genetics.

[6]  W. Herr,et al.  The Oct-2 glutamine-rich and proline-rich activation domains can synergize with each other or duplicates of themselves to activate transcription , 1994, Molecular and cellular biology.

[7]  H. Zoghbi,et al.  The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract. , 2001, Human molecular genetics.

[8]  J. Inostroza,et al.  Transcriptional repression by Msx-1 does not require homeodomain DNA-binding sites , 1995, Molecular and cellular biology.

[9]  R M Winter,et al.  Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[10]  U. Hansen,et al.  Active repression mechanisms of eukaryotic transcription repressors. , 1996, Trends in genetics : TIG.

[11]  Denis Duboule,et al.  Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs , 1993, Cell.

[12]  S. Carroll,et al.  Pleiotropic functions of a conserved insect-specific Hox peptide motif , 2005, Development.

[13]  J. Lis,et al.  DNA distortion and multimerization: novel functions of the glutamine-rich domain of GAGA factor. , 1999, Journal of molecular biology.

[14]  Dimitri Krainc,et al.  Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease , 2002, Science.

[15]  R. Tjian,et al.  Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. , 1989, Science.

[16]  T. Tanimura,et al.  Color Atlas of Fetal Skeleton of the Mouse, Rat, and Rabbit , 1996 .

[17]  R. Guigó,et al.  Comparative analysis of amino acid repeats in rodents and humans. , 2004, Genome research.

[18]  D. Duboule,et al.  The Hox-4.8 gene is localized at the 5′ extremity of the Hox-4 complex and is expressed in the most posterior parts of the body during development , 1991, Mechanisms of Development.

[19]  E. A. O'neill,et al.  The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain , 1989, Cell.

[20]  Sean B. Carroll,et al.  Evolution of a transcriptional repression domain in an insect Hox protein , 2002, Nature.

[21]  D. Mortlock,et al.  Evolution of N-terminal sequences of the vertebrate HOXA13 protein , 2000, Mammalian Genome.

[22]  H. Garner,et al.  Molecular origins of rapid and continuous morphological evolution , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Hayakawa,et al.  Nucleotide compositional constraints on genomes generate alanine-, glycine-, and proline-rich structures in transcription factors. , 1997, Molecular biology and evolution.

[24]  D. Wilkinson.  In situ hybridization: a practical approach , 1998 .

[25]  P. Robinson,et al.  A molecular pathogenesis for transcription factor associated poly-alanine tract expansions. , 2004, Human molecular genetics.

[26]  J. Thompson,et al.  The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. , 1997, Nucleic acids research.

[27]  Jonathan D. Licht,et al.  Drosophila Krüppel protein is a transcriptional represser , 1990, Nature.

[28]  Huda Y. Zoghbi,et al.  Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles , 2005, Nature Reviews Genetics.

[29]  Y. Kino,et al.  Intracellular Localization of Homopolymeric Amino Acid-containing Proteins Expressed in Mammalian Cells* , 2004, Journal of Biological Chemistry.

[30]  Lucia Y Brown,et al.  Alanine tracts: the expanding story of human illness and trinucleotide repeats. , 2004, Trends in genetics : TIG.

[31]  Richard J. Edwards,et al.  Tandem repeat copy-number variation in protein-coding regions of human genes , 2005, Genome Biology.

[32]  R. Tjian,et al.  A Glutamine-Rich Trail Leads to Transcription Factors , 2002, Science.

[33]  I. Kanazawa,et al.  Polar amino acid-rich sequences bind to polyglutamine tracts. , 1998, Biochemical and biophysical research communications.

[34]  H Green,et al.  Codon reiteration and the evolution of proteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[35]  L. Donahue,et al.  A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly. , 1998, Human molecular genetics.

[36]  N. Saitou,et al.  Class III POU genes: Generation of homopolymeric amino acid repeats under GC pressure in mammals , 1996, Journal of Molecular Evolution.

[37]  Yusuke Nakamura,et al.  An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis , 2005, Nature Genetics.

[38]  C. Tabin,et al.  Analysis of Hoxd-13 and Hoxd-11 misexpression in chick limb buds reveals that Hox genes affect both bone condensation and growth. , 1997, Development.

[39]  John M. Hancock,et al.  Simple sequence repeats in proteins and their significance for network evolution. , 2005, Gene.

[40]  R. Behringer,et al.  Manipulating the Mouse Embryo: A Laboratory Manual , 2002 .

[41]  S. Mundlos,et al.  Altered Growth and Branching Patterns in Synpolydactyly Caused by Mutations in HOXD13 , 1996, Science.

[42]  J. Whisstock,et al.  Functional insights from the distribution and role of homopeptide repeat-containing proteins. , 2005, Genome research.

[43]  D. Duboule,et al.  The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes. , 2001, Developmental biology.