Advertisement
JOURNAL ARTICLES
Inner ear and maternal reproductive defects in mice lacking the Hmx3 homeobox gene
W. Wang, T. Van De Water, T. Lufkin
Development 1998 125: 621-634;

Summary

The Hmx homeobox gene family is of ancient origin, being present in species as diverse as Drosophila, sea urchin and mammals. The three members of the murine Hmx family, designated Hmx1, Hmx2 and Hmx3, are expressed in tissues that suggest a common functional role in sensory organ development and pregnancy. Hmx3 is one of the earliest markers for vestibular inner ear development during embryogenesis, and is also upregulated in the myometrium of the uterus during pregnancy. Targeted disruption of the Hmx3 gene results in mice with abnormal circling behavior and severe vestibular defects owing to a depletion of sensory cells in the saccule and utricle, and a complete loss of the horizontal semicircular canal crista, as well as a fusion of the utricle and saccule endolymphatic spaces into a common utriculosaccular cavity. Both the sensory and secretory epithelium of the cochlear duct appear normal in the Hmx3 null animals. The majority of Hmx3 null females have a reproductive defect. Hmx3 null females can be fertilized and their embryos undergo normal preimplantation development, but the embryos fail to implant successfully in the Hmx3 null uterus and subsequently die. Transfer of preimplantation embryos from mutant Hmx3 uterine horns to wild-type pseudopregnant females results in successful pregnancy, indicating a failure of the Hmx3 null uterus to support normal post-implantation pregnancy. Molecular analysis revealed the perturbation of Hmx, Wnt and LIF gene expression in the Hmx3 null uterus. Interestingly, expression of both Hmx1 and Hmx2 is downregulated in the Hmx3 null uterus, suggesting a hierarchical relationship among the three Hmx genes during pregnancy.

REFERENCES

    1. Acampora D.,
    2. Mazan S.,
    3. Avantaggiato V.,
    4. Barone P.,
    5. Tuorto F.,
    6. Lallemand Y.,
    7. Brulet P.,
    8. Simeone A.
    (1996) Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nature Genetics 14, 218–222
    OpenUrlCrossRefPubMedWeb of Science
    1. Benson G. V.,
    2. Lim H. J.,
    3. Paria B. C.,
    4. Satokata I.,
    5. Dey S. K.,
    6. Maas R. L.
    (1996) Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development 122, 2687–2696
    OpenUrlAbstract
    1. Bhatt H.,
    2. Brunet L. J.,
    3. Stewart C. L.
    (1991) Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc. Nat. Acad. Sci. USA 88, 11408–12
    OpenUrlAbstract/FREE Full Text
    1. Bober E.,
    2. Baum C.,
    3. Braun T.,
    4. Arnold H. H.
    (1994) A novel NK- related mouse homeobox gene: expression in central and peripheral nervous structures during embryonic development. Dev. Biol 162, 288–303
    OpenUrlCrossRefPubMedWeb of Science
    1. Carpenter E. M.,
    2. Goddard J. M.,
    3. Chisaka O.,
    4. Manley N. R.,
    5. Capecchi M. R.
    (1993). Loss of Hox-A1 (Hox-1.6) function results in the reorganization of the murine hindbrain. Development 118, 1063–1075
    OpenUrlAbstract/FREE Full Text
    1. Chisaka O.,
    2. Musci T. S.,
    3. Capecchi M. R.
    (1992). Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature 355, 516–520
    OpenUrlCrossRefPubMedWeb of Science
    1. Chomczynski P.,
    2. Sacchi N.
    (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem 162, 156–159
    OpenUrlCrossRefPubMedWeb of Science
    1. Corey D. P.,
    2. Breakefield X. O.
    (1994) Transcription factors in inner ear development. Proc. Nat. Acad. Sci. USA 91, 433–436
    OpenUrlFREE Full Text
    1. Cross J. C.,
    2. Werb Z.,
    3. Fisher S. J.
    (1994) Implantation and the placenta: key pieces of the development puzzle. Science 266, 1508–1518
    OpenUrlAbstract/FREE Full Text
    1. Deitcher D. L.,
    2. Fekete D. M.,
    3. Cepko C. L.
    (1994) Asymmetric expression of a novel homeobox gene in vertebrate sensory organs. J. Neurosci 14, 486–498
    OpenUrlAbstract
    1. Erkman L.,
    2. McEvilly R. J.,
    3. Luo L.,
    4. Ryan A. K.,
    5. Hooshmand F.,
    6. O'Connell S. M.,
    7. Keithley E. M.,
    8. Rapaport D. H.,
    9. Ryan A. F.,
    10. Rosenfeld M. G.
    (1996). Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature 381, 603–606
    OpenUrlCrossRefPubMed
    1. Fekete D. M.
    (1996) Cell fate specification in the inner ear. Curr. Opin. Neurobiol 6, 533–541
    OpenUrlCrossRefPubMedWeb of Science
    1. Frasch M.,
    2. Chen X.,
    3. Lufkin T.
    (1995) Evolutionary-conserved enhancers direct region-specific expression of the murine Hoxa-1 and Hoxa-2 loci in both mice and Drosophila. Development 121, 957–974
    OpenUrlAbstract
    1. Gavin B. J.,
    2. McMahon J. A.,
    3. McMahon A. P.
    (1990) Expresssion of multiple novel Wnt-1/int-1- related genes during fetal and adult mouse development. Genes Dev 4, 2319–2332
    OpenUrlAbstract/FREE Full Text
    1. Gendron R. L.,
    2. Paradis H.,
    3. Hsieh-Li H. M.,
    4. Lee D. W.,
    5. Potter S. S.,
    6. Markoff E.
    (1997) Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biol. Reprod 56, 1097–1105
    OpenUrlAbstract
    1. George K. M.,
    2. Leonard M. W.,
    3. Roth M. E.,
    4. Lieuw K. H.,
    5. Kioussis D.,
    6. Grosveld F.,
    7. Engel J. D.
    (1994) Embryonic expression and cloning of the murine GATA-3 gene. Development 120, 2673–86
    OpenUrlAbstract/FREE Full Text
    1. Gossler A.,
    2. Doetschman T.,
    3. Korn R.,
    4. Serfling E.,
    5. Kemler R.
    (1986) Transgenesis by means of blastocyst-derived embryonic stem cells lines. Proc. Nat. Acad. Sci. USA 83, 9065–9069
    OpenUrlAbstract/FREE Full Text
    1. Huguet E. L.,
    2. Smith K.,
    3. Bicknell R.,
    4. Harris A. L.
    (1995) Regulation of Wnt5a mRNA expression in human mammary epithelial cells by cell shape, confluence and hepatocyte growth factor. J. Biol. Chem 270, 12851–12856
    OpenUrlAbstract/FREE Full Text
    1. Ikegawa S.,
    2. Kumano Y.,
    3. Okui K.,
    4. Fujiwara T.,
    5. Takahashi E.,
    6. Nakamura Y.
    (1996) Isolation, characterization and chromosomal assignment of the human WNT7A gene. Cytogenet. Cell Genet 74, 149–152
    OpenUrlPubMedWeb of Science
    1. Ko L. J.,
    2. Yamamoto M.,
    3. Leonard M. W.,
    4. George K. M.,
    5. Ting P.,
    6. Engel J. D.
    (1991) Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer. Mol. Cell Biol 11, 2778–2784
    OpenUrlAbstract/FREE Full Text
    1. Kuhlman J.,
    2. Niswander L.
    (1997) Limb deformity proteins: role in mesodermal induction of the apical ectodermal ridge. Development 124, 133–139
    OpenUrlAbstract
    1. Li C. W.,
    2. Van De Water T. R.,
    3. Ruben R. J.
    (1978) The fate mapping of the eleventh and twelfth day mouse otocyst: an in vitro study of the sites of origin of the embryonic inner ear sensory structures. J. Morphol 157, 249–267
    OpenUrlCrossRefPubMedWeb of Science
    1. Li C. W.,
    2. Van De Water T. R.,
    3. Ruben R. J.
    (1976) In vitro study of fate mapping of the mouse otocyst. Trans. Am. Acad. Ophthalmol. Otolaryngol 82, 273–280
    OpenUrlPubMed
    1. Li X.,
    2. Wang W.,
    3. Lufkin T.
    (1997) Dicistronic lacZ and alkaline phosphatase reporter constructs permit simultaneous histological analysis of expression from multiple transgenes. BioTechniques 23, 874–882
    OpenUrlPubMed
    1. Lufkin T.
    (1997) Transcriptional regulation of mammalian Hox genes during embryogenesis. Crit. Rev. Eukar. Gene Exp 7, 193–213
    OpenUrl
    1. Lufkin T.,
    2. Dierich A.,
    3. LeMeur M.,
    4. Mark M.,
    5. Chambon P.
    (1991). Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 66, 1105–1119
    OpenUrlCrossRefPubMedWeb of Science
    1. Lufkin T.,
    2. Lohnes D.,
    3. Mark M.,
    4. Dierich A.,
    5. Gorry P.,
    6. Gaub M. P.,
    7. LeMeur M.,
    8. Chambon P.
    (1993) High postnatal lethality and testis degeneration in retinoic acid receptormutant mice. Proc. Nat. Acad. Sci. USA 90, 7225–7229
    OpenUrlAbstract/FREE Full Text
    1. Mark M.,
    2. Lufkin T.,
    3. Vonesch J.,
    4. Ruberte E.,
    5. Olivo J.,
    6. Dolle P.,
    7. Gorry P.,
    8. Lumsden A.,
    9. Chambon P.
    (1993) Two rhombomeres are altered in Hoxa-1 mutant mice. Development 119, 319–338
    OpenUrlAbstract
    1. Martinez P.,
    2. Davidson E. H.
    (1997) SpHmx, a sea urchin homeobox gene expressed in embryonic pigment cells. Dev. Biol 181, 213–222
    OpenUrlCrossRefPubMedWeb of Science
    1. Miano J. M.,
    2. Cserjesi P.,
    3. Ligon K. L.,
    4. Periasamy M.,
    5. Olson E. N.
    (1994) Smooth muscle myosin heavy chain exclusively marks the smooth muscle lineage during mouse embryogenesis. Circ. Res 75, 803–812
    OpenUrlAbstract/FREE Full Text
    1. Nagy A.,
    2. Gocza E.,
    3. Diaz E. M.,
    4. Prideaux V. R.,
    5. Ivanyi E.,
    6. Markkula M.,
    7. Rossant J.
    (1990) Embryonic stem cells alone are able to support fetal development in the mouse. Development 110, 815–821
    OpenUrlAbstract/FREE Full Text
    1. Nusse R.,
    2. Varmus H. E.
    (1992) Wnt genes. Cell 69, 1073–1087
    OpenUrlCrossRefPubMedWeb of Science
    1. Olson E. N.,
    2. Arnold H. H.,
    3. Rigby P. W.,
    4. Wold B. J.
    (1996) Know your neighbors: three phenotypes in null mutants of the myogenic bHLH gene MRF4. Cell 85, 1–4
    OpenUrlCrossRefPubMedWeb of Science
    1. Parr B. A.,
    2. McMahon A. P.
    (1995) Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature 374, 350–353
    OpenUrlCrossRefPubMed
    1. Pavlova A.,
    2. Boutin E.,
    3. Cunha G.,
    4. Sassoon D.
    (1994). Msx1 (Hox-7.1) in the adult mouse uterus: cellular interactions underlying regulation of expression. Development 120, 335–346
    OpenUrlAbstract
    1. Rijli F. M.,
    2. Dolle P.,
    3. Fraulob V.,
    4. LeMeur M.,
    5. Chambon P.
    (1994) Insertion of a targeting construct in a Hoxd-10 allele can influence the control of Hoxd-9 expression. Dev. Dyn 201, 366–377
    OpenUrlCrossRefPubMedWeb of Science
    1. Rinkwitz-Brandt S.,
    2. Arnold H. H.,
    3. Bober E.
    (1996) Regionalized expression of Nkx5-1, Nkx5-2, Pax2 and sek genes during mouse inner ear development. Hear. Res 99, 129–138
    OpenUrlCrossRefPubMedWeb of Science
    1. Rinkwitz-Brandt S.,
    2. Justus M.,
    3. Oldenettel I.,
    4. Arnold H. H.,
    5. Bober E.
    (1995). Distinct temporal expression of mouse Nkx-5.1 and Nkx-5.2 homeobox genes during brain and ear development. Mech. Dev 52, 371–381
    OpenUrlCrossRefPubMedWeb of Science
    1. Sanger F.,
    2. Nicklen S.,
    3. Coulson A. R.
    (1977) DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA 74, 5463–5467
    OpenUrlAbstract/FREE Full Text
    1. Satokata I.,
    2. Benson G.,
    3. Maas R.
    (1995) Sexually dimorphic sterility phenotypes in Hoxa10 -deficient mice. Nature 374, 460–463
    OpenUrlCrossRefPubMedWeb of Science
    1. Shen M. M.,
    2. Leder P.
    (1992) Leukemia inhibitory factor is expressed by the preimplantation uterus and selectively blocks primitive ectoderm formation in vitro. Proc. Nat. Acad. Sci. USA 89, 8240–8244
    OpenUrlAbstract/FREE Full Text
    1. Sidow A.
    (1996) Gen(om)e duplications in the evolution of vertebrates. Curr. Opin. Genet. Dev 6, 715–722
    OpenUrlCrossRefPubMedWeb of Science
    1. Small K. M.,
    2. Potter S. S.
    (1993) Homeotic transformations and limb defects in Hox A11 mutant mice. Genes Dev 7, 2318–2328
    OpenUrlAbstract/FREE Full Text
    1. Stadler H. S.,
    2. Murray J. C.,
    3. Leysens N. J.,
    4. Goodfellow P. J.,
    5. Solursh M.
    (1995) Phylogenetic conservation and physical mapping of members of the H6 homeobox gene family. Mammalian Genome 6, 383–388
    OpenUrlCrossRefPubMed
    1. Stadler H. S.,
    2. Padanilam B. J.,
    3. Buetow K.,
    4. Murray J. C.,
    5. Solursh M.
    (1992). Identification and genetic mapping of a homeobox gene to the 4p16.1 region of human chromosome 4. Proc. Nat. Acad. Sci. USA 89, 11579–11583
    OpenUrlAbstract/FREE Full Text
    1. Stadler H. S.,
    2. Solursh M.
    (1994) Characterization of the homeobox-containing gene GH6 identifies novel regions of homeobox gene expression in the developing chick embryo. Dev. Biol 161, 251–262
    OpenUrlCrossRefPubMedWeb of Science
    1. Stahl J.,
    2. Gearing D. P.,
    3. Willson T. A.,
    4. Brown M. A.,
    5. King J. A.,
    6. Gough N. M.
    (1990) Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions. J. Biol. Chem 265, 8833–8841
    OpenUrlAbstract/FREE Full Text
    1. Stark K.,
    2. Vainio S.,
    3. Vassileva G.,
    4. McMahon A. P.
    (1994) Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683
    OpenUrlCrossRefPubMedWeb of Science
    1. Stein K. F.,
    2. Huber S. A.
    (1960) Morphology and behavior of waltzer-type mice. J. Morphol 106, 197–203
    1. Stewart C. L.
    (1994) Leukaemia inhibitory factor and the regulation of pre-implantation development of the mammalian embryo. Mol. Reprod. Dev 39, 233–238
    OpenUrlCrossRefPubMedWeb of Science
    1. Stewart C. L.,
    2. Kaspar P.,
    3. Brunet L. J.,
    4. Bhatt H.,
    5. Gadi I.,
    6. Kontgen F.,
    7. Abbondanzo S. J.
    (1992) Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359, 76–79
    OpenUrlCrossRefPubMedWeb of Science
    1. Tribioli C.,
    2. Frasch M.,
    3. Lufkin T.
    (1997) Bapx1: an evolutionary-conserved homologue of the Drosophila bagpipe homeobox gene is expressed in splanchnic mesoderm and the embryonic skeleton. Mech. Dev 65, 145–162
    OpenUrlCrossRefPubMedWeb of Science
    1. Van De Water T. R.,
    2. Represa J.
    (1991) Tissue interactions and growth factors that control development of the inner ear. Neural tube-otic anlage interaction. Ann. NY Acad. Sci 630, 116–128
    OpenUrlPubMed
    1. Wang G. V. L.,
    2. Dolecki G. J.,
    3. Carlos R.,
    4. Humphreys T.
    (1990) Characterization and expression of two sea urchin homeobox sequences. Dev. Genet 11, 77–87
    OpenUrlCrossRefPubMed
    1. Wang W.,
    2. Chen X.,
    3. Xu H.,
    4. Lufkin T.
    (1996) Msx3: a novel murine homologue of the Drosophila msh homeobox gene restricted to the dorsal embryonic central nervous system. Mech. Dev 58, 203–215
    OpenUrlCrossRefPubMedWeb of Science
Back to top

 Download PDF

Email
JOURNAL ARTICLES
Inner ear and maternal reproductive defects in mice lacking the Hmx3 homeobox gene
W. Wang, T. Van De Water, T. Lufkin
Development 1998 125: 621-634;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Alerts

Article navigation

Other journals from The Company of Biologists

Advertisement

Kathryn Virginia Anderson (1952-2020)

Developmental geneticist Kathryn Anderson passed away at home on 30 November 2020. Tamara Caspary, a former postdoc and friend, remembers Kathryn and her remarkable contribution to developmental biology.

Zooming into 2021

In a new Editorial, Editor-in-Chief James Briscoe and Executive Editor Katherine Brown reflect on the triumphs and tribulations of the last 12 months, and look towards a hopefully calmer and more predictable year.

Read & Publish participation extends worldwide

Over 60 institutions in 12 countries are now participating in our Read & Publish initiative. Here, James Briscoe explains what this means for his institution, The Francis Crick Institute. Find out more and view our full list of participating institutions.

Upcoming special issues

Imaging Development, Stem Cells and Regeneration
Submission deadline: 30 March 2021
Publication: mid-2021

The Immune System in Development and Regeneration
Guest editors: Florent Ginhoux and Paul Martin
Submission deadline: 1 September 2021
Publication: Spring 2022

Both special issues welcome Review articles as well as Research articles, and will be widely promoted online and at key global conferences.

Development presents...

Our successful webinar series continues into 2021, with early-career researchers presenting their papers and a chance to virtually network with the developmental biology community afterwards. Sign up to join our next session:

10 February
Time: 13:00 (GMT)
Chaired by: preLights