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Molecular and Cellular Biology, March 2004, p. 2074-2082, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.2074-2082.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Defective Neural Tube Closure and Anteroposterior Patterning in Mice Lacking the LIM Protein LMO4 or Its Interacting Partner Deaf-1

Kyungmin Hahm,1,2,{dagger} Eleanor Y. M. Sum,3 Yuko Fujiwara,1 Geoffrey J. Lindeman,3 Jane E. Visvader,3 and Stuart H. Orkin1,2*

Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital and Dana-Farber Cancer Institute,1 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115,2 VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia3

Received 10 November 2003/ Accepted 13 November 2003

LMO4 belongs to a family of transcriptional regulators that comprises two zinc-binding LIM domains. LIM-only (LMO) proteins appear to function as docking sites for other factors, leading to the assembly of multiprotein complexes. The transcription factor Deaf-1/NUDR has been identified as one partner protein of LMO4. We have disrupted the Lmo4 and Deaf-1 genes in mice to define their biological function in vivo. All Lmo4 mutants died shortly after birth and showed defects within the presphenoid bone, with 50% of mice also exhibiting exencephaly. Homeotic transformations were observed in Lmo4-null embryos and newborn mice, but with incomplete penetrance. These included skeletal defects in cervical vertebrae and the rib cage. Furthermore, fusions of cranial nerves IX and X and defects in cranial nerve V were apparent in some Lmo4-/- and Lmo4+/- mice. Remarkably, Deaf-1 mutants displayed phenotypic abnormalities similar to those observed in Lmo4 mutants. These included exencephaly, transformation of cervical segments, and rib cage abnormalities. In contrast to Lmo4 nullizygous mice, nonexencephalic Deaf-1 mutants remained healthy. No defects in the sphenoid bone or cranial nerves were apparent. Thus, Lmo4 and Deaf-1 mutant mice exhibit overlapping as well as distinct phenotypes. Our data indicate an important role for these two transcriptional regulators in pathways affecting neural tube closure and skeletal patterning, most likely reflecting their presence in a functional complex in vivo.

* Corresponding author. Mailing address: Division of Hematology-Oncology, Children's Hospital and Dana-Farber Cancer Institute, Department of Pediatrics, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3564. Fax: (617) 632-4367. E-mail: Stuart_Orkin{at}dfci.harvard.edu.

{dagger} Present address: Biogen Idec, Exploratory Science, Cambridge, MA 02142.

Molecular and Cellular Biology, March 2004, p. 2074-2082, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.2074-2082.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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