Disease relevance of lgl

• The allelic mouse mutations inversus viscerum (iv) and legless (lgl) produce LR inversion, or situs inversus, in half of live-born homozygotes [1].
• This early hypersensitivity of fore- and hindlimbs was followed by a period of reduced sensitivity (Day 8 forelimb; Day 9 hindlimb) when even very high doses (50 mg/kg) induced minimal changes in the typical legless malformation pattern [2].

High impact information on lgl

• Hindlimbs were uniformly truncated at the distal end of the femur, resulting in a "legless" appearance [3].
• Consistent with this, complementation tests confirm allelism of lgl and iv and suggest that the transgene insertion may have disrupted more than one gene [4].
• Phylogenetically conserved sequences flanking the transgene insertions were identified and used to isolate candidate lgl and iv cDNAs [4].
• In this report we describe the developmental expression and function of Sp8, a member of the Sp family of zinc finger transcription factors, and provide evidence that the legless transgene insertional mutant is a hypomorphic allele of the Sp8 gene [5].
• The resulting left-right phenotype, randomization of laterality, is identical to that of iv and lgl mutants [6].

Biological context of lgl

• Posterior truncations were particularly noteworthy, showing a graded response in which frequency and severity of truncation were worst in lgl/lgl fetuses; heterozygotes gave an intermediate response, and wild-type fetuses were least affected [2].
• The Jagged2 gene maps to chromosome 12 and is a candidate for the lgl and sm mutations [7].
• This exacerbation of the legless phenotype by exogenous retinoic acid coupled with the similarity between legless and retinoid malformations suggest that the legless mutation has altered endogenous retinoid homeostasis or a downstream retinoid-responsive gene [2].
• Enhanced expression of limb malformations and axial skeleton alterations in legless mutants by transplacental exposure to retinoic acid [2].
• We have characterized the early stages of murine hindlimb morphogenesis in the legless (lgl)mutant and non-mutant littermates [8].

Anatomical context of lgl

• In lgl, the expression of these genes is initiated but not maintained and the disto-ventral marginal ectoderm does not thicken [8].
• The limb mesenchyme of lgl and non-mutant embryos initially expresses lmx-1b and fgf-10 uniformly [8].
• Correlation of forelimb malformation asymmetries with visceral organ situs in the transgenic mouse insertional mutation, legless [9].
• The control of asymmetry in visceral development appears to be random in the legless mutant; that is, 50% develop normally (situs solitus) and 50% develop with inverted viscera (situs inversus) [9].

Associations of lgl with chemical compounds

• Surprisingly, the altered malformation patterns induced by retinoic acid in lgl mutants were nearly identical to those from earlier, pre-emergence exposure [2].
• Exacerbation of limb malformations in legless (lgl) homozygotes by retinoic acid (RA) [10].
• This manuscript reports on the limb malformations and axial skeleton alterations found in legless fetuses and their heterozygote and wild-type littermates transplacentally exposed to all-trans-retinoic acid via a single intraperitoneal injection on Day 7, 8, 9, 9.5, 10, 10.5, or 11 of gestation [2].

Other interactions of lgl

• In legless, a mouse mutant exhibiting both limb and left/right patterning defects, Gja1 transcripts could not be detected in this region [11].

References