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. 2005 Apr 26;102(17):5913-9.
doi: 10.1073/pnas.0501071102. Epub 2005 Mar 8.

Analysis of mouse embryonic patterning and morphogenesis by forward genetics

María J García-García  1 , Jonathan T Eggenschwiler, Tamara Caspary, Heather L Alcorn, Michael R Wyler, Danwei Huangfu, Andrew S Rakeman, Jeffrey D Lee, Evan H Feinberg, John R Timmer, Kathryn V Anderson
Affiliations

Analysis of mouse embryonic patterning and morphogenesis by forward genetics

María J García-García et al. Proc Natl Acad Sci U S A. .

Abstract

Many aspects of the genetic control of mammalian embryogenesis cannot be extrapolated from other animals. Taking a forward genetic approach, we have induced recessive mutations by treatment of mice with ethylnitrosourea and have identified 43 mutations that affect early morphogenesis and patterning, including 38 genes that have not been studied previously. The molecular lesions responsible for 14 mutations were identified, including mutations in nine genes that had not been characterized previously. Some mutations affect vertebrate-specific components of conserved signaling pathways; for example, at least five mutations affect previously uncharacterized regulators of the Sonic hedgehog (Shh) pathway. Approximately half of all of the mutations affect the initial establishment of the body plan, and several of these produce phenotypes that have not been described previously. A large fraction of the genes identified affect cell migration, cellular organization, and cell structure. The findings indicate that phenotype-based genetic screens provide a direct and unbiased method to identify essential regulators of mammalian development.

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Figures

Fig. 1.
Fig. 1.
New ENU induced alleles of previously characterized genes. (A and B) DD1 is an allele of Tbx6. e10.5 wild-type (A) and DD1 homozygous (B) embryos, assayed by in situ hybridization of the primitive streak marker Brachyury. Mesenchymal cells accumulate in the tail bud of DD1 mutants (B, arrowhead). This phenotype is identical to that observed in Tbx6 mutants (18), and in DD1/Tbx6 heterozygotes (not shown). The Tbx6DD1 mutation was associated with an A to C substitution in the splice acceptor of Tbx6 exon 3 that led to an abnormally spliced product lacking the DNA binding domain. (C and D) M1un is an allele of Pten. In contrast with e9.5 wild-type littermates (C, lateral view), PtenM1un/Ptennull embryos (D, dorsal view) fail to undergo embryonic turning, have broad open headfolds (arrowhead), and cardia bifida (asterisks indicate the two laterally positioned heart fields).
Fig. 2.
Fig. 2.
Mutants with altered dorsal-ventral patterning of the neural tube. Morphological phenotype of whole wild-type (A), Smobnb (B), Disp1icb (C), wim (D), Polarisflexo (E), lln (F), Kif3a2A (G), hnn (H), open brain (I) and sopb (J) embryos. B, C, and G are e9.5 and A, D, E, F, H, I, and J are e10.5 embryos. All these mutants have abnormal brain morphology and show abnormal laterality of heart looping (visible in lln; empty arrowhead in F), and several show exencephaly and spina bifida (arrowheads in D, F, H, I, and J). The effects on dorsal-ventral neural tube patterning are illustrated in the corresponding lower panels (A′-J′), which show the pattern of expression Pax6 in transverse sections of the neural tube. Pax6 is a marker of lateral neural cell types in wild-type embryos (A). Pax6 is expressed throughout the neural tube of bnb and icb mutants (B′ and C′), is shifted ventrally in wim and lln mutants (D′ and F′), is nearly normal in flexo mutants (E′), and is restricted to the dorsal neural tube in hnn, open brain, and sopb mutants (H′, I′, and J′).
Fig. 3.
Fig. 3.
Early morphogenesis mutants that arrest during gastrulation. The morphology of the primitive streak was assayed by in situ hybridization with Brachyury. In contrast to wild-type e7.5 embryos (A), lzme embryos (B) have ectopic cells in the amniotic cavity (arrowhead) and express Brachyury weakly. The morphology of dimple mutant embryos (C) appears normal at e7.5, but they have a laterally expanded domain of Brachyury expression.
Fig. 4.
Fig. 4.
Early morphogenesis mutants that arrest before embryonic turning. Shown are wild-type (A), khlo (B), and lulu (C) embryos assayed for expression of Mox1, a paraxial mesoderm marker. Both khlo and lulu embryos arrest at e9.0, showing abnormal morphogenesis. khlo mutants express Mox1 along the A-P axis (arrowhead in B), although only a few somites can be seen morphologically. In contrast, lulu mutants never differentiate somites, and expression of Mox1 is limited to a small patch of cells (arrowhead in C). The arrow in B points to the accumulation of cells at the primitive streak characteristic of khlo mutants. A is a lateral view of a e9.5 wild-type embryo; B and C are dorsal views of the mutants that have been magnified ×1.3 with respect to A.
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Comment in

  • Biography of Kathryn V. Anderson.
    Trivedi B. Trivedi B. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5910-2. doi: 10.1073/pnas.0501900102. Epub 2005 Apr 19. Proc Natl Acad Sci U S A. 2005. PMID: 15840717 Free PMC article. No abstract available.

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