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Overview

Lmx1a is a member of the LIM-homeodomain subfamily (LIM-HD), characterized by two specialized protein binding zinc fingers, the LIM domains, located N-terminal of the DNA binding homeodomain[1]. Twelve mammalian LIM-HD proteins have been identified, which can be subdivided into six subgroups based on their sequence similarities[1].

Among the six subgroups, the Lmx subgroup has two members: Lmx1a and Lmx1b. Lmx1a was first cloned in hamster as a protein interacting with the E47 bHLH transcription factor to activate the insulin expression in pancreatic cells[2]. Lmx1a is widely expressed in the developing embryo, including the roof plate of the neural tube, the cerebellum, ventral midbrain, otic vesicles, the notochord and the developing pancreas[2][3]. Its roles in the developing nervous system have been studied in dreher mice which harbor mutations in Lmx1a[4]. dreher mutant phenotypes include hearing, pigmentation, skeletal, and neurological abnormalities associated with requirement of Lmx1a in these areas[5]. Embryonic studies of the dreher mutant CNS revealed that Lmx1a is required for roof plate formation in the spinal cord and the fourth ventricle[6]. The roof plate is a signaling center required to specify dorsal CNS cell fates. As a result of loss of the roof plate, dreher mice have abnormalities in the dorsal CNS development including abnormal specification and differentiation of spinal cord dI1 interneurons and severely disrupted cerebellar formation[7]. Lmx1a is both necessary and sufficient for roof plate development, since overexpression can induce ectopic roof plate[8][9]. Beyond the roof plate, Lmx1a has a role in specifying the fates of a subset of hindbrain rhombic lip cells which also significantly contributes to the abnormal cerebellar phenotype in dreher mutants[10]. A number of other roles have been defined for this genes in development. Lmx1a is required for specification of dopaminergic cells of the midbrain[11]. More recent studies have defined its role in the developing inner ear[12][13]. Lmx1a may also act as a supressor of metastasis[14].

References
  1. Hobert O and Westphal H. Functions of LIM-homeobox genes. Trends Genet., 16(2):75-83. (PMID 10652534)
  2. German MS et al. Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex. Genes Dev., 6(11):2165-76. (PMID 1358758)
  3. Failli V et al. Expression of the LIM-homeodomain gene Lmx1a (dreher) during development of the mouse nervous system. Mech. Dev., 118(1-2):225-8. (PMID 12351192)
  4. Chizhikov V et al. Molecular definition of an allelic series of mutations disrupting the mouse Lmx1a (dreher) gene. Mamm. Genome, 17(10):1025-32. (PMID 17019651)
  5. Manzanares M et al. Dorsal patterning defects in the hindbrain, roof plate and skeleton in the dreher (dr(J)) mouse mutant. Mech. Dev., 94(1-2):147-56. (PMID 10842066)
  6. Millonig JH et al. The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature, 403(6771):764-9. (PMID 10693804)
  7. Millen KJ et al. Roof plate and dorsal spinal cord dl1 interneuron development in the dreher mutant mouse. Dev. Biol., 270(2):382-92. (PMID 15183721)
  1. Chizhikov VV et al. The roof plate regulates cerebellar cell-type specification and proliferation. Development, 133(15):2793-804. (PMID 16790481)
  2. Chizhikov VV and Millen KJ. Control of roof plate formation by Lmx1a in the developing spinal cord. Development, 131(11):2693-705. (PMID 15148302)
  3. Chizhikov VV et al. Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem. Proc. Natl. Acad. Sci. U.S.A., 107(23):10725-30. (PMID 20498066)
  4. Andersson E et al. Identification of intrinsic determinants of midbrain dopamine neurons. Cell, 124(2):393-405. (PMID 16439212)
  5. Nichols DH et al. Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis. Cell Tissue Res. (PMID 18985389)
  6. Koo SK et al. Lmx1a maintains proper neurogenic, sensory, and non-sensory domains in the mammalian inner ear. Dev. Biol., 333(1):14-25. (PMID 19540218)
  7. Liu CY et al. Characterization of LMX-1A as a metastasis suppressor in cervical cancer. J. Pathol., 219(2):222-31. (PMID 19644956)
Figures
FIGURE 1 Schematic of LIM-HD proteins
LIM-HD proteins are characterized by two protein binding LIM domains located N-terminal of DNA binding homeodomain. Within the Lmx group, amino acid sequence of the LIM domains are 64% and 84% identical, and the homeodomain is 100% identical.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.