Professor

Department of Cell and Molecular Biology

Tulane University

New Orleans, LA 70118

kmuneoka@tulane.edu

(504) 862-3161 (chair's office); 865-5546 (department office); 865-5554 (lab)

FAX (504) 865-6785

Updated: December, 2004

Limb Development and Regeneration, Morphogenesis, Pattern Formation, Wound Healing, Cell Migration, Growth Control

B.A. 1976 Humboldt State University (Biology/Zoology)

Ph.D. 1983 University of California, Irvine (Developmental and Cell Biology)

Postdoc - 1983-1986 - Developmental Biology Center, University of California Irvine.

Positions Held:

1998 - Present - Professor, Department of Cell and Molecular Biology, Tulane University.

1993 - Present - Chair, Department of Cell and Molecular Biology, Tulane University.

1999 - Present - Director, Department of Cell and Molecular Biology Master of Science Graduate Program, Tulane University

1992-1998 - Associate Professor, Department of Cell and Molecular Biology, Tulane University.

1997 - Visiting Professor, Japan Society for the Promotion of Science Fellowship, Department of Biology, Tohoku, Japan

1990 - Visiting Professor, Department of Brain and Cognitive Sciences, MIT.

1986-1992 - Assistant Professor, Department of Biology, Tulane University.

Teaching Experience:

Tulane University - 1986-Present, Faculty
Embryology Lecture (Undergraduate)
Embryology Lab (Undergraduate)
Cell Biology (Undergraduate)
Cell Biology Lab (Undergraduate)
Advanced Developmental and Cellular Biology (Graduate)

University of California Irvine - 1979-1983, Teaching Assistant
Physiology
Developmental and Cell Biology
Embryology

University of Hawaii - 1977-1979, Teaching Assistant
Animal Physiology
Environmental Physiology
Embryology
Experimental Embryology.

Society for Developmental Biology

American Society for Cell Biology

AAAS

American Association of Anatomist

2004 – present – Editorial board, BMC Developmental Biology

2004 – DARPA Workshop in Accelerated Injury Repair – Invited Participant

2003 - 2004 – NIH Study Section – DEV1 - Member

2003 - Elected Fellow, American Association for the Advancement of Science

1998 - 2003 - Advisory Board Member, United States Veterans Administration Office of Regeneration Research Programs

2002 – 2003 – NIH Study Section – CDF4 - Member

2001 – Panel Member, National Science Foundation, Integrative Graduate Education and Research Traineeship (IGERT) review Panel.

2000 - United States Department of Defense Certificate of Appreciation, Secretary of Defense, William Cohen

1994 - 2000 - Division Editor, Developmental Biology, Journal of Experimental Zoology

1997 - 1999 - Advisory Board Member, United States Department of Defense, Army Science Board

1998 - Invited Participant, EPA Workshop: “Biologically based dose-response modeling for developmental toxicity”, Triangle Park, North Carolina 

1998 - Co-Organizer, NSF Workshop: “Amphibian Malformations”, San Diego, California

1997 - Japan Society for the Promotion of Science Fellowship

1993 - 1996 - Developmental Biology, Associate Editor

1993 - 1995 - NIH Study Section - Cell Biology and Physiology - Member

1993 - Marcus Singer Award

1992 - 1994 - J. of Experimental Zoology, Assistant Editor, Developmental Biology

1991 - 1993 - Co-Director, Grad. Prog. in Molecular and Cellular Biology, Tulane Univ.

1988 - 1993 - NIH Study Section - Cell Biology and Physiology - Ad Hoc Member

1983 - 1984 - PHS Postdoctoral Training Grant Award - University of California Irvine, .

1981 - 1983 - PHS Predoctoral Training Grant Award - University of California Irvine

1982 - American Society of Zoologists - Best Student Paper - Developmental Biology

1981 - University of California Chancellors Patent Fund Award

1979 - Earle C. Anthony Fellowship Award

1978 - Embryology Course, MBL, Woods Hole, MA - NIH Predoc. Training Grant Award

National Institute of Genetics, Mishima, Japan - 1981.

West Coast Regional Developmental Biology Conference, Pacific Grove, CA - 1983.

4th Biennial Forum on Regeneration, Urbana, IL - 1983

Society for Developmental Biology, Workshop on Mammalian Regeneration, Irvine, CA - 1983.

California State University at Chico, Department of Biology, Chico, CA - 1983.

National Science Foundation Workshop on Limb Regeneration, Santa Cruz, CA - 1985.

University of Nevada at Reno, Department of Biology, Reno, NV - 1985.

British Society for Developmental Biology, London, England - 1985.

University of Houston, Department of Biology, Houston, TX - 1986.

Emory University, Department of Biology, Atlanta, GA - 1986.

Worcester Institute of Experimental Biology, Worcester, MA - 1986.

American Society of Zoologist Annual Meeting, Symp. on Intercalation, Nashville, TN - 1986.

Workshop on Limb Development and Regeneration, Santa Fe, New Mexico - 1988.

NATO workshop - Recent Advances in Limb Regeneration - Athens, Greece - 1988.

Workshop on Limb Development and Regeneration, Oceanside, CA - 1989.

Monsanto Company, St. Louis, MO - 1989.

Southwest Developmental Biology Conference Annual Meeting, Fort Worth, TX - 1989.

American Association of Anatomist Annual Meeting - New Orleans, LA - 1989.

Workshop on Limb Development and Regeneration, Dauphin Island, AL - 1990.

Harvard School of Medicine, Department of Genetics, Boston, MA - 1990.

Texas Christian University, Department of Biology, Dallas, TX - 1990.

University of Houston, Department of Biology, Houston, TX - 1990.

Tulane Medical School, Department of Pharmacology, New Orleans, LA - 1991.

Workshop on Limb Development and Regeneration, Idlewilde, CA - 1991.

4th International Conference on Limb Development and Regeneration, Asilomar, CA - 1992

Middle Atlantic Reproduction and Teratology Association, Lake Harmony, PA - 10/92.

Tulane Medical School, Dept. of Biochemistry, New Orleans, LA - 1993.

Workshop on Limb Development and Regeneration, Waveland, MS - 1993.

Marcus Singer Symposium, Irvine, CA - 1993

Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH - 1994.

Tulane Medical School, Department of Physiology, New Orleans, LA - 1994.

FASEB Summer Conference, Repair and Regeneration, Saxtons River, VT. - 1994.

Southwestern Medical Center, Department of Developmental Biology, Dallas Texas, - 1995.

Mount Sinai Medical Center, Brookdale Ctr. for Molecular Biology, New York, NY, - 1995.

Marcus Singer Symposium, London, England - 1996.

5th International Conference on Limb Development and Regeneration, York, England - 1996

Central North America Amphibian Deformities, EPA Workshop, Deluth, MN - 1996

Loyola University, Department of Biology, New Orleans, LA - 1997

Taniguchi Symposium on Developmental Biology VIII, Hong Kong - 1997

Tulane Medical School, Department of Anatomy, New Orleans, LA 1997

Evaluating Amphibian Malformations, EPA Workshop, Shenandoah Nat’l Park, VA - 1997

Tokyo Medical and Dental University, Tokyo Japan - 1997

Department of Biology, Tohoku University, Sendai Japan - 1997

Department of Biological Science & Technology, Tokushima Univ., Tokushima, Japan - 1997

Asamushi Marine Biology Lab, Asamushi, Japan - 1997

Amphibian Malformations Retreat, UC Irvine, Oceanside, CA - 1997

MSGSA Symposium, University of Calgary, Calgary, Canada - 1998

6th Internat’l Conference on Limb Development and Regeneration, Sun Valley, Idaho – 1998

Department of Biology, Tohoku University, Sendai Japan - 1998

MSGSA Symposium on Regeneration, University of Calgary, Calgary, Canada - 1998

EPA Symposium: “Biochemical, Genetic  and  Molecular Mechanisms of Skeletal Development”, Triangle Park, North Carolina - 2000

10^th International Symposium on Neural Regeneration, Asilomar, CA - 2003

Biocomplexity IV: Regenerative Biology and Medicine, Bloomington, IN - 2003

Regeneration Workshop, London England - 2003

FASEB Meeting Symposium: “Growth and Development”, American Association of Anatomist symposium, New Orleans, Louisiana - 2002

Regenerate 2004, Tissue Engineering the Human Body, Seattle, WA - 2004

Muneoka, K. (1980). A new method for mechanical dechorionation of ascidian eggs. Develop. Biol. 74, 486-489.

Muneoka, K. and Bryant, S.V. (1982). Evidence that patterning mechanisms in developing and regenerating limbs are the same. Nature 298, 369-371.

Muneoka, K., Fox, W.F., and Bryant, S.V. (1982). Modified bismuth staining procedure for axolotl tissue. Axolotl Newsletter, 12, 2-7.

Iten, L.E., Murphy, D.J., and Muneoka, K. (1983). Do chick limb bud cells have positional information? In: "Limb Development and Regeneration, Part A." (J.F. Fallon and A. I. Caplan, eds,), pp. 77-88. Alan R. Liss, Inc., New York.

Muneoka, K., and Bryant, S. V. (1984). Cellular contribution to supernumerary limbs in the axolotl, Ambystoma mexicanum. Develop. Biol. 105, 166-78.

Muneoka, K., and Bryant, S. V. (1984). Cellular contribution to supernumerary limbs resulting from the interaction between developing and regenerating tissues in the axolotl. Develop. Biol. 105, 179-187.

Muneoka, K., Wise, L. D., Fox, W. F., and Bryant, S. V. (1984). Improved techniques for use of the triploid cell marker in the axolotl, Ambystoma mexicanum. Develop. Biol. 105, 240-245.

Muneoka, K. and Bryant, S.V. (1984). Regeneration and development of vertebrate appendages. Symp. zool. Soc. Lond. 52, 177-196.

Muneoka, K.,Holler-Dinsmore, G.V. and Bryant, S.V. (1985). A quantitative analysis of regeneration from chimeric limb stumps in the axolotl. J. Embryol. Exp. Morph. 90, 1-12.

Muneoka, K., Holler-Dinsmore, G.V. and Bryant, S.V. (1986). Regneration from discontinuous circumferences in axolotl limbs. In: "Progress in Developmental Biology, Part A" (ed. H.C. Slavkin) Alan R. Liss, Inc., p. 61-65.

Muneoka, K., Wanek, N. and Bryant, S.V. (1986). Exo utero survival of mouse embryos. In: "Progress in Developmental Biology, Part A" (ed. H.C. Slavkin). Alan R. Liss, Inc., p. 305-308.

Bryant, S.V. and Muneoka, K. (1986). Views on limb development and regeneration. Trends in Genetics 2(6), 153-159.

Muneoka, K., Holler-Dinsmore, G.V. and Bryant, S.V. (1986). Pattern discontinuity, polarity and directional intercalation in axolotl limbs. J. Embryol. and Exp. Morph. 93, 51-72.

Muneoka, K., Fox, W.F. and Bryant, S.V. (1986). Cellular contribution from dermis and catilage to the regenerating limb blastema in axolotls. Develop. Biol. 116, 256-260.

Muneoka, K., Wanek, N. and Bryant, S.V. (1986). Mouse embryos develop normally exo utero. J. Exp. Zool. 239, 289-293.

Muneoka, K., Holler-Dinsmore, G.V. and Bryant, S.V. (1986). Intrinsic control of regenerative loss during limb development in Xenopus laevis. J. Exp. Zool. 240, 47-54.

Gardiner, D.M., Muneoka, K. and Bryant, S.V. (1986). The migration of dermal cells during blastema formation in axolotls. Develop. Biol. 118, 488-493.

Bryant, S.V., Muneoka, K. and Gardiner, D.M. (1987). Cellular interactions in vertebrate limb patterning. In: "Advances in Gene Technology: The Molecular Biology of Development." (W. Voellmy, F. Ahmad, S. Black, D. Burgess, R. Rotundo, W. Scott and W. Whelan, eds.) Cambridge University Press, Cambridge, United Kingdom. pp. 130-131.

Muneoka, K. and Murad, E.G. (1987). Intercalation and the cellular origin of supernumerary limbs in Xenopus. Development 99, 521-526.

Bryant, S.V., Gardiner, D.M. and Muneoka, K. (1987). Limb development and regeneration. Am. Zool. 27, 675-696.

Wanek, N., Muneoka, K., Burton, R., Holler-Dinsmore, G. and Bryant, S.V. (1989). A staging system for mouse limb development. J. Exp. Zool. 249, 41-49.

Muneoka, K., Wanek, N. and Bryant, S.V. (1989). Mammalian limb bud development: In situ fate maps of early hindlimb buds. J. Exp. Zool. 249, 50-54.

Wanek, N., Muneoka, K. and Bryant, S.V. (1989). Evidence for regulation following amputation and tissue grafting in the developing mouse limb. J. Exp. Zool. 249, 55-61.

Muneoka, K., Bryant, S.V. and Gardiner, D.M. (1989). Growth control in limb regeneration. In: "Developmental Biology of the Axolotl." (J. Armstrong and G. Malacinski eds.) Oxford University Press, Oxford, United Kingdom, p. 143-156.

Armstrong, J.B. and Muneoka, K. (1989). Genetic markers and their use in chimeras. In: "Developmental Biology of the Axolotl." (J. Armstrong and G. Malacinski eds.) Oxford University Press, Oxford, United Kingdom, p. 236-243.

Muneoka, K., Wanek, N., Trevino, C. and Bryant, S.V. (1990). Exo utero surgery. In: "Post-Implantation Mammalian Embryo." (A. Copp and D. Cockroft eds.) IRL Press, Oxford, England, pp. 41-60.

Wanek, N., Gardiner, D.M., Muneoka, K. and Bryant, S.V. (1991). Retinoic acid changes anterior cells into ZPA cells in the chick wing bud. Nature, 350, 81-83. (News and Views - p. 15).

Tabin, C.J., Morgan, B., Simon, H-G, Lazar, S., Wang, Y., Iyer, A., Yaglom, J., Shi, C., Muneoka, K., and Sassoon, D. (1991). Functional studies of genes in the limb. In: Limb Patterning. (Hinchliffe, R., Hurle, J. and Summerbell, D. eds.) Plenum Press, New York, NY, p. 45-54.

Synder, D.C., Coltman, B.W., Muneoka, K. and Ide, C.F. (1991). Mapping the early projections from the entorhinal cortex in the embryonic mouse using prenatal surgery techniques. J. Neurobiol. 22(9), 897-906.

Trevino, C., Calof, A. and Muneoka, K. (1992). Position specific growth regulation of 3T3 cells in the developing mouse limb. Develop. Biol. 150, 72-81.

Shi, C. and Muneoka, K. (1992). Position specific growth of mouse limb bud cells in vitro. Develop. Biol. 151, 9-17.

Muneoka, K. and Sassoon, D. (1992). Regeneration in developing vertebrate limbs. Develop. Biol. 152, 37-49.

Trevino, C., Anderson, R. and Muneoka, K. (1993). 3T3 cell integration and differentiative potential during limb development in the mouse. Develop. Biol. 155, 38-45.

Anderson, R., Landry, M. and Muneoka, K. (1993). In vitro maintenance of posterior (ZPA) signaling in Mouse limb bud cells. In: "4th International Conference on Limb Development and Regeneration." (Eds. P. Goetinck, J. Fallon, D. Stocum, R. Kelley). John Wiley and Sons, Inc. New York. pp. 371-380.

Trevino, C., Anderson, R., Landry, M., Koenig, G., Tonthat, B., Shi, C., and Muneoka, K. (1993). MPLB-2: A posterior signaling cell line derived from the mouse limb bud. In: "4th International Conference on Limb Development and Regeneration." (Eds. P. Goetinck, J. Fallon, D. Stocum, R. Kelley). John Wiley and Sons, Inc. New York. pp. 295-304.

Anderson, R., Landry, M. and Muneoka, K. (1993). Maintenance of ZPA signaling in cultured mouse limb bud cells. Development 117, 1421-1433.

Hayamizu, T.F., Wanek, N., Taylor, G., Trevino, C., Shi, C., Anderson, R., Gardiner, D.M., Muneoka, K. and Bryant, S.V. (1994) Develop. Biol. 161, 504-512.

Taylor, G.P., Anderson, R., Reginelli, A.D. and Muneoka, K. (1994). FGF-2 induces regeneration of the chick limb bud. Develop. Biol. 163, 282-284.

Anderson, R., Landry, M., Reginelli, A., Taylor, G., Achkar, C., Gudas, L., and Muneoka, K. (1994). Conversion of anterior limb bud cells to ZPA signaling cells in vitro and in vivo. Dev. Biol. 164, 241-257.

Reginelli, A.D., Wang, Y., Sassoon, D., and Muneoka, K. (1995). Digit tip regeneration correlates with regions of msx1 (formerly Hox7) expression in fetal and newborn mice. Development 121, 1065-1076.

Li, S., Anderson, R., Reginelli, A.D. and Muneoka, K. (1996). FGF-2 modifies gene expression and cell mobility during limb development in the chick. J. Exp. Zool. 274, 234-247.

Muneoka, K. and Anderson, R. (1997). Limb Development. In: "Drug Toxicity in Embryonic Development I" R.J. Kavlock and G.P. Daston eds. Springer-Verlag pp 41-75.

Muneoka, K. (1998). 50 Years of Limb Development. (K. Muneoka, Ed.) Special Issue of J. Exp. Zool. 282 (6), 627-738.

Muneoka, K (1998). Researching the limb: 50 years later. J. Exp. Zool. 282, 627.

Ngo-Muller, V. and Muneoka, K. (1999). Exo Utero Surgery. In: "Developmental Biology Protocols, Vol.1" R.S. Tuan and C.W. Lo eds. Humana Press Inc., Totowa, New Jersey. pp 481-492.

Muller, T.L., Ngo-Muller, V., Reginelli, A., Taylor, G., Anderson, R. and Muneoka, K. (1999). Regeneration in higher vertebrates: Limb buds and digit tips. Sem. Cell & Develop. Biol., 10, 405-413.

Li, S. and Muneoka, K. (1999). Cell migration and chick limb development: chemotactic action of FGF-4 and the AER. Develop. Biol., 211, 335-347.

Ngo-Muller, V. and Muneoka, K. (2000). Influence of FGF4 on digit morphogenesis during limb development in the mouse. Develop. Biol., 219, 224-236. 

Schaller, S., Li, S., Ngo-Muller, V., Han, M-J., Omi, M., Anderson, R. and Muneoka, K. (2000). Cell Biology of Limb Patterning. Internat’l. Rev. Cytology (in press).

Lau, C., Andersen, M.E., Crawford-Brown, D.J., Kavlock, R.J., Kimmel, C.A., Knudsen, T.B., Muneoka, K., Rogers, J.M., Setzer, R.W., Smith, G., and Tyl, R. (2000). Evaluation of biologically based dose-response modeling for developmental toxicity: A workshop report. Regulatory Toxicology and Pharmacology (in press).

Schaller, S., and Muneoka, K.  (2001).  Inhibition of polarizing activity in the anterior limb bud is regulated by extracellular factors.  Dev. Biol., 240, 443-456.  

Omi, M., Anderson, R. & Muneoka, K. (2002). Differential cell affinity and sorting of anterior and posterior cells during outgrowth of recombinant avian limb buds.  Develop. Biol. 250, 292-304.

Han, M., Yang, X., Farrington, J.E. & Muneoka, K. (2003).  Digit regeneration is regulated by Msx1 and BMP4 in fetal mice.  Development 130, 5123-5132.

Ngo-Muller, V., Li, S., Schaller, S.A., Han M., Farrington, J., Omi, M., Anderson, R., & Muneoka, K. (2004).  FGF4 and Skeletal Morphogenesis.  In: The Skeleton, Biochemical, Genetic,  and Molecular Interactions in Development and Homeostasis  (E.J. Massaro, J.M. Rogers, Eds), Humana Press, Totowa, New Jersey. pp 131-145.

Muneoka, K. (1985). Book review of "Cell and Tissue Regeneration: A Biochemical Approach" by M.B. Ord and L.A. Stocken. BioEssays 2(4), 188.

Muneoka, K. (1986). Book review of "Regulation of Vertebrate Limb Regeneration" by R.E. Sicard (ed.). The Quarterly Review of Biology 61(4), 548.

2004 marks my 25^th year carrying out research in the field of vertebrate limb formation.  During that time I have utilized a number of experimental models including the regenerating salamander limb, the regenerating mouse digit, and the developing limbs of salamanders, frogs, chicks and mice.  I have remained both productive and actively funded during this time.  My studies have primarily focused on how cells communicate with one another to establish the 3-dimensional pattern of the adult limb.  I have been lucky enough to be a participant in a field that has undergone an amazing transformation to become the best understood developing vertebrate organ, and to witness the limb system gain prominence in many aspects of applied science ranging from teratology to ecology. 

The limb is formed by a series of interactions that occur between a specialized group of ectodermal cells at the tip of the limb bud that forms a structure called the apical ectodermal ridge (AER), and the mesenchymal cells that underlie the AER.  The apical ectoderm produces factors that are necessary for distal outgrowth by the mesenchyme.  Mesenchymal cells interact with one another and with the AER to establish spatially distinct patterns of gene expression followed by the differentiation of specific structures.  The primary focus of my research is to understand how cells become distinct from one another.  In the 1980’s my cell lineage work on developing and regenerating amphibian limbs demonstrated similarities between development and regeneration, and also established the over-contribution of fibroblasts in the regeneration response.  To begin to address regeneration in higher vertebrates, I pioneered in utero surgical techniques that make it possible to carry out regeneration studies on the developing mammalian limb. In the early 1990’s I participated with Susan Bryant’s lab in a study that demonstrated retinoic acid acted to induce a mesenchymal signaling center in the limb bud called the Zone of Polarizing Activity (ZPA).  This finding has now been demonstrated with loss of function studies and with more sophisticated molecular probes with the same conclusion. 

Seminal Contributions:

Muneoka, K. and Bryant, S.V. (1982).  Evidence that patterning mechanisms in developing and regenerating limbs are the same.  Nature 298, 369-371.

Muneoka, K., and Bryant, S. V. (1984).  Cellular contribution to supernumerary limbs resulting from the interaction between developing and regenerating tissues in the axolotl.  Develop. Biol. 105, 179-187.

Muneoka, K., Fox, W.F. and Bryant, S.V. (1986).  Cellular contribution from dermis and cartilage to the regenerating limb blastema in axolotls.  Develop. Biol. 116, 256-260.

Muneoka, K., Wanek, N. and Bryant, S.V. (1986).  Mouse embryos develop normally exo utero.  J. Exp. Zool. 239, 289-293.

Wanek, N., Gardiner, D.M., Muneoka, K. and Bryant, S.V. (1991).  Retinoic acid changes anterior cells into ZPA cells in the chick wing bud.  Nature, 350, 81-83.

Studies from my lab established an initial link between the production of fibroblast growth factors (FGF) by the AER and the signaling ability of the ZPA.  Signaling by the ZPA is now known to be mediated by a secreted factor called sonic hedgehog (Shh) and it is now well-established that FGFs modulate Shh production. Since that time we have continued to focus on FGF signaling and our studies have focused on how FGFs modify positional characteristics of non-ZPA cells and how FGFs modulate limb outgrowth.  We have shown that FGFs can induce a regenerative response from the non-regenerating chick limb bud and we have gone on to show that FGF-4 functions as a chemotactic factor produced by the AER to regulate cell movements important for limb morphogenesis.  We have also shown that limb bud cells possess differential cell adhesive properties that influence cell behavior during limb morphogenesis. The idea that cell motility and differential cell adhesion plays a critical role in limb morphogenesis leading to outgrowth is novel for the field and we have proposed a dynamic model for this process.  

FGFs are secreted factors that interact with specific cell surface receptors to elicit a response.  One of the feastures of the FGF family is that they have an affinity for heparan sulfate moieties present in the extracellular matrix (ECM.  We have investigated the role of ECM during limb development utilizing the ZPA signaling assay in the chick limb bud.  The ZPA signaling assay is based on the stimulation of supernumerary digits following tissue grafts into the anterior limb bud.  Historically, the ZPA is identified and characterized based on its ability to induce supernumerary digits and more recently, there is evidence that the production of SHH by ZPA cells is responsible for this induction. Using this assay we have discovered that ECM preparations from a number of cell lines have the ability to induce supernumerary digits in the absence of ectopic SHH.  Remarkably, we find that stripping the ECM preparation of bound factors enhances signaling levels suggesting that this activity involved the inactivation of inhibitory activity in the limb bud. These studies are truly unique in that they represent the first experimental evidence that ECM components are playing a key role in modulating cell-cell signaling during limb development. 

Seminal Contributions:

Anderson, R., Landry, M. and Muneoka, K. (1993).  Maintenance of ZPA signaling in cultured mouse limb bud cells.  Development  117, 1421-1433.

Anderson, R., Landry, M., Reginelli, A., Taylor, G., Achkar, C., Gudas, L., and Muneoka, K. (1994).  Conversion of anterior limb bud cells to ZPA signaling cells in vitro and in vivo.  Develop. Biol. 164, 241-257.

Li, S. and Muneoka, K. (1999). Cell migration and chick limb development: chemotactic action of FGF-4 and the AER.  Develop. Biol., 211, 335-347.

Schaller, S and Muneoka, K. (2001).  Inhibition of polarizing activity in the anterior limb bud is regulated by extracellular factors.  Develop. Biol., 240, 443-456.

Omi, M., Anderson, R. & Muneoka, K. (2002). Differential cell affinity and sorting of anterior and posterior cells during outgrowth of recombinant avian limb buds.  Develop. Biol. 250, 292-304.

Ngo-Muller, V., Li, S., Schaller, S.A., Han M., Farrington, J., Omi, M., Anderson, R., & Muneoka, K. (2004).  FGF4 and Skeletal Morphogenesis.  In: The Skeleton, Biochemical, Genetic,  and Molecular Interactions in Development and Homeostasis  (E.J. Massaro, J.M. Rogers, Eds), Humana Press, Totowa, New Jersey. pp 131-145.

Our FGF studies have been extended to the developing mouse limb where we have discovered that FGF-4 modulates cell movements during digit morphogenesis. In this case, we find that FGF4 induces expansion of the digit tip leading to digit bifurcation. FGFs are known to regulate the expression of the Msx homeobox-containing genes (Msx1 and Msx2) during limb outgrowth, and we show that Msx1 gene expression is expanded in association with digit tip bifurcation. We had previously shown that digit tip regeneration in fetal and neonatal stages correlated with the expression domain of Msx1 in the nail region. In recent studies we have found that mutant mice that lack the Msx1 gene are defective in their ability to regenerate the digit tip. This is the first demonstration of a gene in mammals that is necessary to mount a digit tip regeneration response. Our studies also show that during digit formation the expression of the Bmp4 gene is dependent on Msx1 and Msx2 expression, and that adding BMP4 to amputated Msx1 mutant digits rescues the regeneration response.  Finally, we have shown that inhibiting the activity of BMPs during digit tip regeneration in wildtype mice results in the inhibition of digit tip regeneration.  In sum, our studies identify a signaling cascade that plays a regulatory role in a regeneration response in mammals.  For the regenerating digit, this is the first regulatory signal that has been identified.  Ongoing studies in the lab are following up on this important discovery and additional regulatory signals are being identified.  

Seminal Contributions:

Taylor, G.P., Anderson, R., Reginelli, A.D. and Muneoka, K. (1994).  FGF-2 induces regeneration of the chick limb bud.  Develop. Biol.  163, 282-284.

Reginelli, A.D., Wang, Y., Sassoon, D., and Muneoka, K. (1995).  Digit tip regeneration correlates with regions of msx1 (formerly Hox7) expression in fetal and newborn mice.  Development  121, 1065-1076.

Muller, T.L., Ngo-Muller, V., Reginelli, A., Taylor, G., Anderson, R. and Muneoka, K. (1999).  Regeneration in higher vertebrates:  Limb buds and digit tips.  Sem. Cell & Develop. Biol., 10, 405-413.

Ngo-Muller, V. and Muneoka, K. (2000).  Influence of FGF4 on digit morphogenesis during limb development in the mouse.  Develop. Biol., 219, 224-236.

Han, M., Yang, X., Farrington, J.E. & Muneoka, K. (2003).  Digit regeneration is regulated by Msx1 and BMP4 in fetal mice.  Development 130, 5123-5132.