The long range goals of the proposed research are to better define the developmental and genetic pathways of limb development and the left-right asymmetry determination in mammals. The investigators propose to take advantage of lgl mutant mice in this effort. They propose to study the altered gene expression patterns in lgl mutants to better define the mesenchymal ectodermal interactions required for apical ectodermal ridge (AER) induction. They will generate trans-species recombinant limbs to determine if the lack of AER formation is attributable to defective lgl mesenchyme or ectoderm. Differential display will be used to identify genes misexpressed in lgl which mediate the AER induction process. We also propose to use direct selection to identify additional genes from the deleted region which are expressed in the limb and may be the source of the disruption in this signaling cascade.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Javois, Lorette Claire
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Cincinnati Children's Hospital Medical Center
United States
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Bell, Sheila M; Schreiner, Claire M; Wert, Susan E et al. (2008) R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development 135:1049-58
Bell, Sheila M; Schreiner, Claire M; Waclaw, Ronald R et al. (2003) Sp8 is crucial for limb outgrowth and neuropore closure. Proc Natl Acad Sci U S A 100:12195-200
Valerius, M Todd; Patterson, Larry T; Feng, Yuxin et al. (2002) Hoxa 11 is upstream of Integrin alpha8 expression in the developing kidney. Proc Natl Acad Sci U S A 99:8090-5
Supp, D M; Brueckner, M; Kuehn, M R et al. (1999) Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development 126:5495-504
Bell, S M; Lan, Y; Jiang, R et al. (1998) Exclusion of Jagged2 as a candidate for the legless gene. Mamm Genome 9:778-9
Bell, S M; Schreiner, C M; Scott, W J (1998) The loss of ventral ectoderm identity correlates with the inability to form an AER in the legless hindlimb bud. Mech Dev 74:41-50
Supp, D M; Witte, D P; Potter, S S et al. (1997) Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature 389:963-6
Supp, D M; Witte, D P; Branford, W W et al. (1996) Sp4, a member of the Sp1-family of zinc finger transcription factors, is required for normal murine growth, viability, and male fertility. Dev Biol 176:284-99
Scott, W J; Collins, M D; Ernst, A N et al. (1994) Enhanced expression of limb malformations and axial skeleton alterations in legless mutants by transplacental exposure to retinoic acid. Dev Biol 164:277-89
Schreiner, C M; Scott Jr, W J; Supp, D M et al. (1993) Correlation of forelimb malformation asymmetries with visceral organ situs in the transgenic mouse insertional mutation, legless. Dev Biol 158:560-2

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