Extracellular matrix, Morphogenesis and Human Disorders
Extracellular matrix (ECM) is the inanimate material between and around cells. It provides cells with anchorage, and influences every aspect of their behavior and fate. It is the structural framework on which every tissue and organ is built. It stores and regulates growth factors, is a source of bioactive fragments, and provides the appropriate microenvironment for stem cells. ECM and cell-ECM interactions are relevant to almost every human disease. ECM of the embryo is quite different from the specialized ECM found in adult tissues, and it is provisional, meaning that it is impermanent and rapidly remodeled. Our laboratory studies provisional ECM in embryogenesis and birth defects involving the face, eye, heart, neural tube, blood vessels and limbs. This work is relevant to several human inherited connective tissue disorders as well as to fetal-maternal health and acquired conditions such as arthritis, fibrosis, cataracts, cancer and vascular disorders. We use genetics, biochemistry and cell biology techniques to define mechanisms of ECM assembly and turnover, and to understand how ECM controls cell behavior.
Current laboratory activities:
At its core, the laboratory is interested in how secreted metalloproteinases modify the provisional ECM, and how this, in turn, regulates morphogenesis and influences human disease.We investigate proteinases of the ADAMTS family.Several ADAMTS proteinases and ADAMTS-like proteins were discovered in this laboratory, and we have been investigating their fundamental characteristics and functions for over a decade. We ask: What do they look like? What post-translational modifications render them fully functional? What are their interacting partners and substrates? What are the consequences of their deficiency or excess? How do they participate in formation of tissues and organs? The laboratory benefits from collaboration with several groups around the world to bring diverse expertise to bear on these specific questions.
In a unique operational paradigm, several ADAMTS proteinases (ADAMTS1,4,5,9,20) cooperate physiologically in versican processing. Defective ADAMTS proteolysis of versican is involved in several major birth defects such as cleft palate, neural tube defects and congenital heart defects including ventricular septal defect, valve malformations and Tetralogy of Fallot. The laboratory devotes considerable effort to understanding versican proteolysis and the role of versican itself in morphogenesis. We are also interested in versican as a potential biomarker for human disorders and for its role in cancer.
Mutations of ADAMTS10, ADAMTS17, ADAMTSL2 and ADAMTSL4 cause related inherited connective tissue disorders. Among the anomalies some of them share is disruption of the ocular zonule, a fibrillin-rich structure that suspends the lens in the optic path. This anomaly, named ectopia lentis, is also common in Marfan syndrome, and it led us to investigate zonule formation and molecular mechanisms of microfibril assembly. We have shown that these ADAMTS proteins bind to fibrillins and regulate their assembly. We presently investigate the molecular mechanisms of these effects.
ADAMTS9, the most conserved of all metalloproteinases, is required for normal eye development and implicated in age-related macular degeneration. The laboratory investigates mechanisms of ocular anterior segment defects arising from ADAMTS9 deficiency that are related to the congenital disorder of glycosylation, Peters Plus syndrome. We investigate ADAMTS9 using conditional and gene trap mutants, and misexpression or inactivation in cells.
We generate recombinant ADAMTS9, as well as other ADAMTS proteins, versican and fibrillins to study their intrinsic properties, post-translational modification, and intermolecular interactions. We are using mass spectrometry to identify ADAMTS substrates.
Research in the laboratory is supported by the National Eye Institute, the NIH-NHLBI Program of Excellence in Glycosciences, the National Institute of Arthritis, Skin and Musculoskeletal Disorders, Sabrina’s Foundation, and the Marfan Foundation.
Selected recent research articles:
1. Nandadasa, S., Nelson, C.M., Apte, SS. ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation. Cell Reports 11:1519-28, 2015
2. Hubmacher D, Wang LW, Mecham RP, Reinhardt DP, Apte SS. Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia: A novel mouse model providing insights on geleophysic dysplasia. Dis Model Mech. 8: 487-499, 2015 PMID: 25762570
3. Collin GB, Hubmacher D, Charette JR, Hicks WL, Stone L, Yu M, Naggert JK, Krebs MP, Peachey NS, Apte SS, Nishina PM. Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. Hum Mol Genet. 2015 Sep 24. pii: ddv399
4. Dubail J, Aramaki-Hattori N, Bader HL, Nelson CM, Katebi N, Matuska B, Olsen BR, Apte SS. A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. Genesis. 2014 52:702-12
5. Foulcer SJ, Nelson CM, Quintero MV, Kuberan B, Larkin J, Dours-Zimmermann MT, Zimmermann DR, Apte SS. Determinants of Versican-V1 Proteoglycan Processing by the Metalloproteinase ADAMTS5. J Biol Chem. 2014, 289(40):27859-73
Recent literature reviews, technical reports and commentaries:
1. Dubail J, Apte SS. Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics.Matrix Biol. 44-46:24-37 2015
2. Foulcer SJ, Day AJ, Apte SS. Isolation and purification of versican and analysis of versican proteolysis. Methods Mol Biol. 1229:587-604, 2015
3. Nandadasa S, Foulcer S, Apte SS. The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis. Matrix Biol. 2014, 35:34-41, 2014.
4. Apte, SS. Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis. Biochem J. 2016 Jan 1;473(1):e1-e4
Recent book chapters:
1. Apte, SS. Chapter 259. Connective Tissue Structure and Function. ed. Goldman L, and Shafer, A.I., Goldman-Cecil Textbook of Medicine, Twenty-Fifth Edition, Elsevier, New York, 2016, ISBN 9781455750177
2. Apte SS. ADAMTS proteases: Mediators of physiological and pathogenic extracellular proteolysis, in Bradshaw, R., and Stahl, P, eds, Encyclopedia of Cell Biology, Elsevier, New York, 2015, ISBN 9780123944474
3. Apte, SS. Chapter 2. Overview of the ADAMTS superfamily, in Rodgers, G., ed, ADAMTS13: Biology and Disease, Springer, New York, 2015, ISBN 9783319087160
4. Traboulsi I, and Apte SS. Chapter 43. Ectopia Lentis and Associated Systemic Disease, in Traboulsi, I., ed, Genetic Diseases of the Eye, Second Edition, Oxford University Press, USA, 2012, ISBN 9780195326147
Additional publications from our laboratory are obtainable at http://www.ncbi.nlm.nih.gov/pubmed/
|US Patent||Patent Title||Issue Date||First-Named Inventor|
|6,391,610||Nucleic Acids Encoding Zinc Metalloproteases||5/21/2002||Suneel S. Apte Ph.D|