Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: Evidence for a network of interacting genes

Huimin Yu, Xin Ye, Nini Guo, Jeremy Nathans

Research output: Contribution to journalArticle

Abstract

Frizzled (Fz) 2 and Fz7, together with Fz1, form a distinct subfamily within the Frizzled family of Wnt receptors. Using targeted gene deletion, we show that: Fz7-/- mice exhibit tail truncation and kinking with 100% penetrance and ventricular septal defects (VSDs) with ~15% penetrance; Fz2+/-;Fz7-/- mice exhibit VSDs with ~50% penetrance and cleft palate with less than 10% penetrance; and Fz2-/-;Fz7-/- mice exhibit convergent extension defects and mid-gestational lethality with 100% penetrance. When Fz2 and/or Fz7 mutations are combined with mutations in Vangl2, Dvl3, Wnt3a, Wnt5a or Wnt11, an increased frequency of VSDs is observed with Dvl3, Wnt3a and Wnt11; an increased frequency of palate closure defects is observed with Vangl2; and early lethality and enhanced tail shortening are observed with Wnt5a. To assess the signaling pathways that underlie these and other Frizzled-mediated genetic interactions, we used transfected mammalian cells to analyze (1) canonical Wnt signaling induced by all pairwise combinations of the ten mouse Frizzleds and the 19 mouse Wnts and (2) localization of each Frizzled at cell-cell junctional complexes formed by mouse Celsr1, a likely indicator of competence for planar cell polarity signaling. These in vitro experiments indicate that Fz2 and Fz7 are competent to signal via the canonical pathway. Taken together, the data suggest that genetic interactions between Fz2, Fz7 and Vangl2, Dvl3 and Wnt genes reflect interactions among different signaling pathways in developmental processes that are highly sensitive to perturbations in Frizzled signaling.

Original languageEnglish (US)
Pages (from-to)4383-4394
Number of pages12
JournalDevelopment
Volume139
Issue number23
DOIs
StatePublished - Dec 1 2012

Fingerprint

Ventricular Septum
Palate
Gene Regulatory Networks
Penetrance
Ventricular Heart Septal Defects
Tail
Wnt Receptors
Cell Polarity
Mutation
Gene Deletion
Cleft Palate
Mental Competency
Genes

Keywords

  • Convergent extension
  • Fz2
  • Fz7
  • Planar cell polarity
  • Wnt signaling

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

Cite this

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title = "Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: Evidence for a network of interacting genes",
abstract = "Frizzled (Fz) 2 and Fz7, together with Fz1, form a distinct subfamily within the Frizzled family of Wnt receptors. Using targeted gene deletion, we show that: Fz7-/- mice exhibit tail truncation and kinking with 100{\%} penetrance and ventricular septal defects (VSDs) with ~15{\%} penetrance; Fz2+/-;Fz7-/- mice exhibit VSDs with ~50{\%} penetrance and cleft palate with less than 10{\%} penetrance; and Fz2-/-;Fz7-/- mice exhibit convergent extension defects and mid-gestational lethality with 100{\%} penetrance. When Fz2 and/or Fz7 mutations are combined with mutations in Vangl2, Dvl3, Wnt3a, Wnt5a or Wnt11, an increased frequency of VSDs is observed with Dvl3, Wnt3a and Wnt11; an increased frequency of palate closure defects is observed with Vangl2; and early lethality and enhanced tail shortening are observed with Wnt5a. To assess the signaling pathways that underlie these and other Frizzled-mediated genetic interactions, we used transfected mammalian cells to analyze (1) canonical Wnt signaling induced by all pairwise combinations of the ten mouse Frizzleds and the 19 mouse Wnts and (2) localization of each Frizzled at cell-cell junctional complexes formed by mouse Celsr1, a likely indicator of competence for planar cell polarity signaling. These in vitro experiments indicate that Fz2 and Fz7 are competent to signal via the canonical pathway. Taken together, the data suggest that genetic interactions between Fz2, Fz7 and Vangl2, Dvl3 and Wnt genes reflect interactions among different signaling pathways in developmental processes that are highly sensitive to perturbations in Frizzled signaling.",
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T1 - Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate

T2 - Evidence for a network of interacting genes

AU - Yu, Huimin

AU - Ye, Xin

AU - Guo, Nini

AU - Nathans, Jeremy

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Frizzled (Fz) 2 and Fz7, together with Fz1, form a distinct subfamily within the Frizzled family of Wnt receptors. Using targeted gene deletion, we show that: Fz7-/- mice exhibit tail truncation and kinking with 100% penetrance and ventricular septal defects (VSDs) with ~15% penetrance; Fz2+/-;Fz7-/- mice exhibit VSDs with ~50% penetrance and cleft palate with less than 10% penetrance; and Fz2-/-;Fz7-/- mice exhibit convergent extension defects and mid-gestational lethality with 100% penetrance. When Fz2 and/or Fz7 mutations are combined with mutations in Vangl2, Dvl3, Wnt3a, Wnt5a or Wnt11, an increased frequency of VSDs is observed with Dvl3, Wnt3a and Wnt11; an increased frequency of palate closure defects is observed with Vangl2; and early lethality and enhanced tail shortening are observed with Wnt5a. To assess the signaling pathways that underlie these and other Frizzled-mediated genetic interactions, we used transfected mammalian cells to analyze (1) canonical Wnt signaling induced by all pairwise combinations of the ten mouse Frizzleds and the 19 mouse Wnts and (2) localization of each Frizzled at cell-cell junctional complexes formed by mouse Celsr1, a likely indicator of competence for planar cell polarity signaling. These in vitro experiments indicate that Fz2 and Fz7 are competent to signal via the canonical pathway. Taken together, the data suggest that genetic interactions between Fz2, Fz7 and Vangl2, Dvl3 and Wnt genes reflect interactions among different signaling pathways in developmental processes that are highly sensitive to perturbations in Frizzled signaling.

AB - Frizzled (Fz) 2 and Fz7, together with Fz1, form a distinct subfamily within the Frizzled family of Wnt receptors. Using targeted gene deletion, we show that: Fz7-/- mice exhibit tail truncation and kinking with 100% penetrance and ventricular septal defects (VSDs) with ~15% penetrance; Fz2+/-;Fz7-/- mice exhibit VSDs with ~50% penetrance and cleft palate with less than 10% penetrance; and Fz2-/-;Fz7-/- mice exhibit convergent extension defects and mid-gestational lethality with 100% penetrance. When Fz2 and/or Fz7 mutations are combined with mutations in Vangl2, Dvl3, Wnt3a, Wnt5a or Wnt11, an increased frequency of VSDs is observed with Dvl3, Wnt3a and Wnt11; an increased frequency of palate closure defects is observed with Vangl2; and early lethality and enhanced tail shortening are observed with Wnt5a. To assess the signaling pathways that underlie these and other Frizzled-mediated genetic interactions, we used transfected mammalian cells to analyze (1) canonical Wnt signaling induced by all pairwise combinations of the ten mouse Frizzleds and the 19 mouse Wnts and (2) localization of each Frizzled at cell-cell junctional complexes formed by mouse Celsr1, a likely indicator of competence for planar cell polarity signaling. These in vitro experiments indicate that Fz2 and Fz7 are competent to signal via the canonical pathway. Taken together, the data suggest that genetic interactions between Fz2, Fz7 and Vangl2, Dvl3 and Wnt genes reflect interactions among different signaling pathways in developmental processes that are highly sensitive to perturbations in Frizzled signaling.

KW - Convergent extension

KW - Fz2

KW - Fz7

KW - Planar cell polarity

KW - Wnt signaling

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SN - 0950-1991

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