Analysis of a new allele of limb deformity (ld) reveals tissue- and age-specific transcriptional effects of the Ld Global Control Region.

The mouse limb deformity (ld) phenotype is characterized by developmental failure of distal limb structures often associated with renal anomalies. It is caused by loss of the BMP-antagonist Gremlin in the limb buds, either through mutation of Grem1, or by loss of a transcriptional global control region (GCR) located in the neighboring Fmn1 gene. In this report, we describe a new allele of ld due to complete deletion of Fmn1, including its GCR. Unlike many other ld strains, these mice are viable and fertile as homozygotes. As expected, this genomic deletion causes loss of Gremlin in the developing limb buds, but effects in other tissues are variable. Specifically, Grem1 expression is retained in the developing lung and kidney, whereas expression is lost from the corresponding adult tissues. In contrast, expression in the brain appears to be unaffected by loss of the GCR. To provide information about long-range transcriptional effects of this region, effects of the deletion on the transcription of neighboring genes were also investigated. This analysis revealed that alterations in neighboring genes do occur, but only in a limited fashion. These data indicate that the predominant effect of the Ld GCR is to activate the expression of Grem1 in the developing limb buds, although it may serve a minor role in long-range transcriptional effects that extend beyond Fmn1 and Grem1.