Cranial Suture Development
Murine Model
Zebrafish Model
Our laboratory is interested in understanding the biology governing cranial suture formation, patency, and fusion. Craniosynostosis, the premature fusion of cranial sutures, occurs in approximately 1 in 2000 live births and is associated with significant morbidity and mortality. Currently, cranial-vault remodeling is the only treatment available. We primarily use two models to explore cranial suture biology: 1) programmed postnatal murine suture fusion, and 2) zebra fish cranial development. In the murine model, one suture (the posterior frontal suture) normally fuses while all other sutures remain patent. Taking advantage of this physiologic model, we are comparing and contrasting molecular and cellular profiles of fusing and patent sutures in order to understand the principles of bone formation. Zebrafish (Danrio rerio) have several advantages over other vertebrate models such as mice, chicken, and frogs. For example, Zebrafish have a short gestation and the embryos are easy to manipulate because they develop in a transparent egg (outside of the mother). Current zebrafish projects are directed towards: 1) understanding the genetic mechanisms that create and pattern the skull; 2) identifying specific genes which play essential functions during suture patterning; 3) isolating new gene mutations that are responsible for craniofacial pathology.
Using advanced microsurgical and molecular biologic techniques, our laboratory has made substantial progress in understanding murine cranial suture biology. It is clear that, in murine models, the dura mater acts as an endogenous tissue engineer, providing the biomolecular blueprints that determine the fate of the overlying cranial suture. Utilizing murine and zebra fish models to investigate the fundamental morphogenetic mechanisms of normal cranial biology, we may understand the etiopathogenesis of craniosynostosis and devise targeted therapeutic interventions that can alter the course of this malady. Looking forward into this new millennium, one can imagine a time when major reconstructive surgery for craniosynostosis will no longer be necessary. For example, the use of gene therapeutic techniques may lead to minimally invasive approaches to the treatment of premature cranial suture fusion.
Selected Articles:
Roth DA, Bradley JP, Levine JP, McMullen HF, McCarthy JG, Longaker MT: Studies in Cranial Suture Biology: Part II. Role of the Dura in Cranial Suture Fusion. Plast Reconstr Surg 97: 693-699, 1996.
Levine JP, Bradley JP, Roth DA, McCarthy JG, Longaker MT: Studies in Cranial Suture Biology: Regional Dura Determines Overlying Suture Biology. Plast Reconstr Surg 101: 1441-1447, 1997.
Bradley JP, Levine JP, Blewett C, Krummel T, McCarthy JG, Longaker MT: Studies in Cranial Suture Biology: In Vitro Cranial Suture Fusion. Cleft Palate-Craniofac J 33: 150-156, 1996.
Bradley JP, Levine JP, McCarthy JG, Longaker MT: Studies in Cranial Suture Biology Regional Dura Mater Determines in Vitro Cranial Suture Fusion. Plast Reconstr Surg 100: 1091-1099, 1997.
Roth DA, Longaker MT, McCarthy JG, Rosen DM, McMullen HF, Levine JP, Sung J, Gold LI: Studies in Cranial Suture Biology: Part I. Increased Immunoreactivity for TGF-Beta Isoforms During Rat Cranial Suture Fusion. J Bone and Mineral Res 12: 311-321, 1997.
Roth DA, Gold LI, Han VKM, McCarthy JG, Sung JJ, Wisoff JH, Longaker MT: Immunolocalization of Transforming Growth Factor B1, B2, and B3 and Insulin-like Growth Factor I in Premature Cranial Suture Fusion. Plast Reconstr Surg 99: 300-309.
Most D, Levine JP, Chang J, Sung J, McCarthy JG, Schendel SA, Longaker MT: Studies in Cranial Suture Biology: Upregulation of Transforming Growth Factor Beta-1 and Basic Fibroblast Growth Factor mRNA Correlates with Posterior Frontal Cranial Suture Fusion in the Rat. Plast Reconstr Surg 101: 1431-1440, 1998.
Mehrara BJ, Most D, Chang J, Bresnick S, Turk A, Schendel SA, Gittes GK, Longaker MT: Basic Fibroblast Growth Factor and Transforming Growth Factor Beta-1 Expression in the Developing Dura Mater Correlates with Calvarial Bone Formation. Plast Reconstr Surg 104: 435-444, 1999.
Mehrara BJ, Mackool RJ, McCarthy JG, Gittes GK, Longaker MT: Immunolocalization of Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptor-1 and Receptor-2 in Rat Cranial Sutures. Plast Reconstr Surg 102: 1805-1817, 1998.
Mehrara BJ, Saadeh PB, Steinbrech DS, Dudziak M, Fernandez H, Gittes GK, Longaker MT: Adenovirus-mediated Gene Therapy of Osteoblasts In Vitro and In Vivo. J Bone Mineral Research 14: 1290-1301, 1999.
Mehrara BJ, Most D, Chang J, Bresnick S, Turk A, Schendel SA, Gittes GK, Longaker MT: Basic Fibroblast Growth Factor and Transforming Growth Factor Beta-1 Expression in the Developing Dura Mater Correlates with Calvarial Bone Formation. Plast Reconstr Surg 104: 435-444, 1999.
Mehrara BJ, Saadeh PB, Steinbrech DS, Dudziak M, Fernandez H, Gittes GK, Longaker MT: Adenovirus-mediated Gene Therapy of Osteoblasts In Vitro and In Vivo. J Bone Mineral Research 14: 1290-1301, 1999.
Bradley JP, Han VK, Roth DA, Levine JP, McCarthy JG, Longaker MT: Increased IGF-I and IGF-II mRNA and IGF-I Peptide in Fusing Rat Cranial Sutures Suggests Evidence for a Paracrine Role of Insulin-like Growth Factors in Suture Fusion. Plast Reconstr Surg 104: 129-138, 1999.
Mehrara BJ, Greenwald JA, Chin GS, Dudziak ME, Sagiroglu JS, Steinbrech DS, Saadeh PB, Gittes GK, Longaker MT: Regional Differentiation of Rat Cranial Suture-Derived Dural Cells is Dependent on Association with Fusing and Patent Sutures. Plast Reconstr Surg 104: 1003-1013, 1999.
Mehrara BJ, Steinbrech DS, Saadeh PB, Gittes GK, Longaker MT: Expression of High-Affinity Receptors for TGF-beta During Rat Cranial Suture Fusion. Ann Plast Surg 42: 502-508, 1999.
Greenwald JA, Mehrara BJ, Spector JA, Chin GS, Steinbrech DS, Saadeh PB, Luchs JS, Paccione MF, Gittes GK, Longaker: Biomolecular Mechanisms of Calvarial Bone Induction: Immature vs. Mature Dura Mater. Plast Reconstr Surg 105: 1382-1392, 2000.
Greenwald JA, Mehrara BJ, Spector JA, Fagenholz BJ, Saadeh PB, Steinbrech DS, Gittes GK, Longaker MT: Immature vs Mature Dura Mater: II. Differential Expression of Genes Important to Calvarial Reossification. Plast Reconstr Surg 106: 630-639, 2000.
Spector JA, Mehrara BJ, Greenwald JA, Saadeh PB, Steinbrech DS, Smith LP, Longaker MT: A Molecular Analysis of the Isolated Rat Posterior Frontal and Sagittal Sutures: Differences in Gene Expression. Plast Reconstr Surg 106: 852-861, 2000.
Greenwald JA, Mehrara BJ, Spector JA, Warren SM, Crisera FE, Fagenholz PJ, Longaker MT: Regional Differentiation of Cranial Suture-Associated Dura Mater In Vivo and In Vitro: Implications for Suture Fusion and Patency. J Bone Mineral Research 15: 2413-2430, 2000.
Sagiroglu JS, Mehrara BJ, Chau D, Saadeh PB, Gittes GK, Longaker MT: Analysis of TGF-beta Production by Fusing and Non-fusing Mouse Cranial Sutures In Vitro. Ann Plast Surg 42: 496-501.
Greenwald JA, Mehrara BJ, Spector JA, Warren SM, Fagenholz PJ, Smith LP, Bouletreau PJ, Crisera FE, Ueno H, Longaker MT: In vivo Modulation of FGF-Biologic Activity Alters Cranial Suture Fate. Am J Pathology 158: 441-452, 2001.
Warren SM, Greenwald JA, Spector JA, Bouletreau PJ, Mehrara BJ, Longaker MT: New Developments in Cranial Suture Research. Plast Reconstr Surg 107: 523-540, 2001.
Spector JA, Greenwald JA, Warren SM, Mehrara BJ, Fagenholz PJ, Bouletreau PJ, Crisera FE, Longaker MT: Co-culture of Osteoblasts with Immature Dural Cells Causes an Increased Rate and Degree of Osteoblast Differentiation. Plast Reconstr (Accepted for Publication).
Spector JA, Greenwald JA, Warren SM, Bouletreau PJ, Detch RC, Fagenholz PJ, Crisera FE, Longaker MT: Dura Mater promotes Calvarial Growth and Re-ossification: Autocrine and Paracrine of Fibroblast Growth Factor-2. Plast Reconstr Surg (Accepted for Publication).
Mehrara BJ, Warren SM, Longaker MT: Adenovirus-mediated Transmission of a Dominant Negative Truncated TGF-B Receptor Inhibits In Vitro Mouse Cranial Suture Fusion. Plast Reconstr Surg (Submitted for Publication).
Longaker MT: Role of TGF-B Signaling in the Regulation of Programmed Cranial Suture Fusion. J Craniofac Surg 12: 389-390, 2001.
