Abstract
Dorsal-ventral limb patterning in vertebrates is thought to be controlled by the LIM-homeodomain protein Lmx1b which is expressed in a spatially and temporally restricted manner along the dorsal-ventral limb axis1,2. Here we describe the phenotype resulting from targeted disruption of Lmx1b. Our results demonstrate that Lmx1b is essential for the specification of dorsal limb fates at both the zeugopodal and autopodal level with prominent phenotypes including an absence of nails and patellae. These features are similar to those present in a dominantly inherited human condition called nail patella syndrome3 (NPS) which also has renal involvement. Mouse Lmx1b maps to a region syntenic to that of the NPS gene4, and kidneys of Lmx1b mutant mice exhibit pathological changes similar to that observed in NPS (refs 5,6). Our results demonstrate an essential function for Lmx1b in mouse limb and kidney development and suggest that NPS might result from mutations in the human LMX1B gene.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Riddle, R.D. et al. Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb. Cell 83, 631–640 (1995).
Vogel, A., Rodriguez, C., Warnken, W. & Izpisua Belmonte, J.C. Dorsal cell fate specified by chick Lmx1 during vertebrate limb development. Nature 378, 716–720 (1995).
Jones, K.L. Smith's Recognizable Patterns of Human Malformation, (W.B. Saunders Company, Philadelphia, 1997).
McIntosh, I. et al. Fine mapping of the nail-patella syndrome locus at 9q34. Am. J. Hum. Genet. 60, 133–142 (1997).
Del Pozo, E. & Lapp, H. Ultrastructure of the kidney in the nephropathy of the nail-patella syndrome. Am. J. Clin. Pathol. 54, 845–851 (1970).
Morita, T. et al. Nail-Patella syndrome. Light and electron microscopic studies of the kidney. Arch. Intern. Med. 131, 271–277 (1973).
Sanchez-Garcia, I. & Rabbitts, T.H. The LIM domain: a new structural motif found in zinc-finger-like proteins. Trends Genet. 10, 315–320 (1994).
Johnson, J.D., Zhang, W.G., Rudnick, A., Rutter, W.J. & German, M.S., Transcriptional Synergy Between Lim-Homeodomain Proteins and Basic Helix-Loop-Helix Proteins - the Lim2 Domain Determines Specificity. Mol. Cell. Biol. 17, 3488–3496 (1997).
German, M.S., Wang, J., Chadwick, R.B. & Rutter, W.J. Synergistic activation of the insulin gene by a LIM-homeodomain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex. Genes Dev. 6, 2165–2176 (1992).
Pilz, A., Prohaska, R., Peters, J. & Abbott, C. Genetic linkage analysis of the Ak1, Col5a1, Epb7.2, Fpgs, Grp78, Pbx3, and Notchl genes in the region of mouse chromosome 2 homologous to human chromosome 9q. Genomics 21, 104–109 (1994).
Cygan, J., Johnson, R.L. & McMahon, A.P. Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants. Development 124, 5021–5032 (1997).
Parr, B.A., Shea, M.J., Vassileva, G. & McMahon, A.P., Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Development 119, 247–261 (1993).
Joyner, A.L. & Martin, G.R. En-1 and En-2, two mouse genes with sequence homology to the Drosophila engrailed gene: expression during embryo-genesis [published erratum appears in Genes Dev. 1, 521 (1987)]. Genes Dev. 1, 29–38 (1987).
Parr, B.A. & McMahon, A.P. Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature 374, 350–353 (1995).
Loomis, C.A. et al. The mouse Engrailed-1 gene and ventral limb patterning. Nature 382, 360–363 (1996).
Johnson, R.L. & Tabin, C.J. Molecular models of vertebrate limb development. Cell 90, 979–990 (1997).
Riddle, R.D., Johnson, R.L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 (1993).
Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).
Davis, A.P. & Capecchi, M.R. Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11. Development 120, 2187–2198 (1994).
, S., et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nature Genet. 19, 47–50 (1998)
Lechner, M.S. & Dressier, G.R. The molecular basis of embryonic kidney development. Mech. Dev. 62, 105–120 (1997).
Jurata, L.W. & Gill, G.N. Functional analysis of the nuclear LIM domain interactor NLI. Mol. Cell. Biol. 17, 5688–5698 (1997).
McMahon, A.P. & Bradley, A., Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62, 1073–1085 (1990).
Gan, L. et al. POU domain factor Brn-3b is required for the development of a large set of retinal ganglion cells. Proc. Natl Acad. Sci. USA 93, 3920–3925 (1996).
Chen, Z.F. & Behringer, R.R. twist is required in head mesenchyme for crainial neural tube morphogenesis. Genes Dev. 15, 686–699 (1995).
Hogan, B., Beddington, R., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo: a Laboratory Manual, (Cold Spring Harbor Laboratory Press, Cold Spring Harbour, 1994).
Albrecht, U. et al. Platelet-activating factor acetylhydrolase expression-and activity suggest a link between neuronal migration and platelet-activating factor. Dev. Biol. 180, 579–593 (1996).
Pepicelli, C.V., Kispert, A., Rowitch, D.H. & McMahon, A.P. GDNF induces branching and increased cell proliferation in the ureter of the mouse. Dev. Biol. 192, 193–198 (1997).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, H., Lun, Y., Ovchinnikov, D. et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet 19, 51–55 (1998). https://doi.org/10.1038/ng0598-51
Issue Date:
DOI: https://doi.org/10.1038/ng0598-51
This article is cited by
-
The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report
BMC Musculoskeletal Disorders (2024)
-
Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity
Nature Communications (2021)
-
A novel small deletion of LMX1B in a large Chinese family with nail-patella syndrome
BMC Medical Genetics (2019)
-
Early dorsomedial tissue interactions regulate gyrification of distal neocortex
Nature Communications (2019)