Disease relevance of Grem1

• The expression of IGFBPs and gremlin was measurable in the livers of these mice, whereas it was low or undetectable in control mice without liver fibrosis [1].
• During the evolution of diabetic nephropathy, the secreted BMP antagonist gremlin increased substantially [2].

High impact information on Grem1

• In contrast, our studies establish that the two other ld alleles directly disrupt the neighboring Gremlin gene, corroborating the requirement of this BMP antagonist for limb morphogenesis [3].
• We resolve these conflicting results by identifying a cis-regulatory region within the deletion that is required for Gremlin activation in the limb bud mesenchyme [3].
• Furthermore, genetic interaction of GLI3 and dHAND directs establishment of the SHH/FGF signaling feedback loop by restricting the BMP antagonist GREMLIN posteriorly [4].
• Our data also indicate that although there is not a conserved mechanism for maintaining interdigit tissue across amniotes, the expression in the bat forelimb interdigits of Gremlin and Fgf8 suggests that these key molecular changes contributed to the evolution of the bat wing [5].
• Their establishment is significantly delayed in Grem1-deficient limb buds and cannot be rescued by specific restoration of SHH signalling in mutant limb buds [6].

Biological context of Grem1

• A distinct change in gremlin mRNA compartmentalization occurs during follicle development and ovulation, indicating a highly regulated expression pattern during folliculogenesis [7].
• Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis [8].
• In contrast, the deletion of the corresponding genomic region reproduces the ld limb phenotype and is allelic to mutations in Gremlin [3].
• Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis [9].
• This shows that GREM1/FGF feedback signalling is required for regulation of the temporal kinetics of the mesenchymal response to SHH signalling [6].

Anatomical context of Grem1

• In early limb buds, mesenchymal Grem1 is required to establish a functional apical ectodermal ridge and the epithelial-mesenchymal feedback signaling that propagates the sonic hedgehog morphogen [9].
• Furthermore, Grem1-mediated BMP antagonism is essential to induce metanephric kidney development as initiation of ureter growth, branching and establishment of RET/GDNF feedback signaling are disrupted in Grem1-deficient embryos [9].
• Our microarray analysis has identified gremlin as one of the genes up-regulated by GDF9 in cultures of granulosa cells [7].
• Dan is first seen in the head mesoderm of early head fold stage embryos and Drm is expressed in the lateral paraxial mesoderm at E8 [10].
• This study is the first to show that peripheral benzodiazepine receptor and DRM/gremlin are expressed in preadipocyte cell lines and that they are differentially regulated during adipogenesis [11].

Associations of Grem1 with chemical compounds

• Differential expression of the peripheral benzodiazepine receptor and gremlin during adipogenesis [11].

Regulatory relationships of Grem1

• In addition, in cultures of granulosa cells, gremlin negatively regulates BMP4 signaling but not GDF9 activity [7].
• Shh-expressing cells and their descendants cannot express Gremlin [12].

Other interactions of Grem1

• An ectopic expression of Gremlin found in the transgenic limb bud would be responsible for the ectopic Fgf4 expression [13].
• On the other hand, adenoviral overexpression of gremlin blocked the stimulatory effects of exogenous BMP-4 [8].
• We propose that gremlin modulates the cross-talk between GDF9 and BMP signaling that is necessary during follicle development because both ligands use components of the same signaling pathway [7].
• Growth differentiation factor 9 regulates expression of the bone morphogenetic protein antagonist gremlin [7].
• SP-C/gremlin transgenic mice exhibited a disruption of the proximal-distal patterning found in the airways of the mammalian lung [14].

Analytical, diagnostic and therapeutic context of Grem1

• A Grem1 null mutation in the mouse generated by gene targeting causes neonatal lethality because of the lack of kidneys and lung septation defects [9].
• The expression of gremlin in the ovary was also examined by in situ hybridization [7].

References