Disease relevance of Lmx1b

• Targeted disruption of Lmx1b results in skeletal defects including hypoplastic nails, absent patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal malformation nail patella syndrome (NPS) [1].
• Our results demonstrate that Lmx1b regulates important steps in glomerular development and establish a link between three hereditary kidney diseases: nail-patella syndrome (Lmx1b), steroid-resistant nephrotic syndrome (podocin), and Alport syndrome (collagen IV alpha4) [2].

High impact information on Lmx1b

• We show that two LIM homeodomain transcription factors, Lim1 and Lmx1b, control the initial trajectory of motor axons in the developing mammalian limb [3].
• Here we describe the phenotype resulting from targeted disruption of Lmx1b [4].
• Our results suggest that, during development of 5-HT neurons, Lmx1b is a critical intermediate factor that couples Nkx2-2-mediated early specification with Pet1-mediated terminal differentiation [5].
• A major determinant in the cascades is an LIM homeodomain-containing gene, Lmx1b, which is required for the development of all 5-HT neurons in the central nervous system [5].
• We identified the LIM homeodomain transcription factor Lmx1b in the mesencephalic dopamine (mesDA) systems of embryos and adults [6].

Biological context of Lmx1b

• We suggest a model whereby, in En1 mutants, ectopic ventral Wnt7a and/or Lmx1b expression leads to the transformation of ventral cells in the broadened AER to a more dorsal phenotype [7].
• The downregulation or the absence of alpha3/4(IV) collagen chains in the GBM of Lmx1b(-/-) and Col4a3(-/-) mice was found to induce ectopic deposition of alpha5/6(IV) collagen [8].
• Recently, it has been shown that Lmx1b is expressed in the isthmic region and that it may occupy higher hierarchical position in the gene expression cascade in the isthmus [9].
• Lmx1b is essential for proper patterning and morphogenesis of the calvaria since the supraoccipital and interparietal bones of lmx1b mutant mice are either missing or severely reduced [10].
• The effects of the absence of Lmx1b in the CNS were determined in lmx1b-/- mice by histology and immunocytochemistry [11].

Anatomical context of Lmx1b

• Abnormal localization of Lmx1b-expressing cells in the ventral mesenchyme, along with histological alterations and an abnormal melanization pattern of the limb, indicate altered dorsal-ventral (DV) boundaries [12].
• CNS expression pattern of Lmx1b and coexpression with ptx genes suggest functional cooperativity in the development of forebrain motor control systems [13].
• Lmx1b mutants also exhibit the disruption of the cutaneous afferent ingrowth, suggesting that the dorsal horn cells might provide important cues guiding sensory axons into the dorsal spinal cord [14].
• Lmx1b controls the differentiation and migration of the superficial dorsal horn neurons of the spinal cord [14].
• Lmx1b expression during joint and tendon formation: localization and evaluation of potential downstream targets [15].

Associations of Lmx1b with chemical compounds

• Using antibodies to podocyte proteins important for podocyte function, we found that Lmx1b(-/-) podocytes express near-normal levels of nephrin, synaptopodin, ZO-1, alpha3 integrin, and GBM laminins [16].

Regulatory relationships of Lmx1b

• These data suggest that Wnt7a acts through Lrp6 to regulate Lmx1b expression during dorsal specification [17].
• Furthermore, we demonstrate that the roof plate-inducing activity of Lmx1b can be suppressed by Mash1 (Cash1), which is normally expressed in intermediate neural tube in both chick and mouse [18].

Other interactions of Lmx1b

• 5. In the MHB of Lmx1b(-/-) embryos, the expression of Fgf8, which normally occurs at the 4-somite stage, was completely absent, whereas Wnt1 was downregulated before the 4-somite stage [19].
• Here we show that the LIM homeobox gene Lmx1b is expressed in the anterior embryo as early as E7.5 and its expression becomes progressively restricted to the isthmus at E9 [19].
• By contrast, Otx2 and Pax6 expression was not affected in Lmx1b(-/-) embryos [19].
• In the chick, Lmx1b acts upstream of Lmx1a in the roof plate developmental program [18].

Analytical, diagnostic and therapeutic context of Lmx1b

• In this study, in situ hybridizations of Lmx1b on murine limb sections reveal strong expression in dorsal mesenchymal tissues (precursors of muscle, tendons, joints and patella) and, interestingly, also in anterior structures of the limb, explaining the anterior to posterior gradient of joint and nail dysplasia observed in NPS patients [20].

References