Loss of function but no gain of function caused by amino acid substitutions in the hexapeptide of Hoxa1 in vivo

Sophie Remacle, Leïla Abbas, Olivier De Backer, Nathalie Pacico, Anthony Gavalas, Françoise Gofflot, Jacques J Picard, René Rezsöhazy

Research output: Contribution to journalArticle

Abstract

Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.

Original languageEnglish
Pages (from-to)8567-75
Number of pages9
JournalMolecular Cell Biology
Volume24
Issue number19
DOIs
Publication statusPublished - 2004

Fingerprint

Amino Acid Substitution
Rhombencephalon
Mutation
Proteins
Organogenesis
Cranial Nerves
Transcription Factors

Keywords

  • Amino Acid Substitution
  • Animals
  • Body Patterning
  • Cranial Nerves
  • Ear
  • Homeodomain Proteins
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neural Crest
  • Occipital Bone
  • Peptide Fragments
  • Rhombencephalon
  • Transcription Factors

Cite this

Remacle, Sophie ; Abbas, Leïla ; De Backer, Olivier ; Pacico, Nathalie ; Gavalas, Anthony ; Gofflot, Françoise ; Picard, Jacques J ; Rezsöhazy, René. / Loss of function but no gain of function caused by amino acid substitutions in the hexapeptide of Hoxa1 in vivo. In: Molecular Cell Biology. 2004 ; Vol. 24, No. 19. pp. 8567-75.
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Loss of function but no gain of function caused by amino acid substitutions in the hexapeptide of Hoxa1 in vivo. / Remacle, Sophie; Abbas, Leïla; De Backer, Olivier; Pacico, Nathalie; Gavalas, Anthony; Gofflot, Françoise; Picard, Jacques J; Rezsöhazy, René.

In: Molecular Cell Biology, Vol. 24, No. 19, 2004, p. 8567-75.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of function but no gain of function caused by amino acid substitutions in the hexapeptide of Hoxa1 in vivo

AU - Remacle, Sophie

AU - Abbas, Leïla

AU - De Backer, Olivier

AU - Pacico, Nathalie

AU - Gavalas, Anthony

AU - Gofflot, Françoise

AU - Picard, Jacques J

AU - Rezsöhazy, René

PY - 2004

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N2 - Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.

AB - Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.

KW - Amino Acid Substitution

KW - Animals

KW - Body Patterning

KW - Cranial Nerves

KW - Ear

KW - Homeodomain Proteins

KW - Mice

KW - Mice, Transgenic

KW - Mutation

KW - Neural Crest

KW - Occipital Bone

KW - Peptide Fragments

KW - Rhombencephalon

KW - Transcription Factors

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JF - Molecular Cell Biology

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