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KENRO KUSUMI Associate Professor Ph.D., Massachusetts Institute of Technology Send e-mail to kenro@asu.edu

Developmental Genetics, Functional Genomics and Human Genetics

The research of my lab is focused on studying the early development of the spine, and finding the genetic causes of vertebral birth defects. The vertebral column derives from embryonic precursors called somites, which are formed in a process regulated by a “segmentation clock.” Although we know that genes in the notch and wnt signaling pathways are involved in the segmentation clock, the regulatory machinery of this clock is not fully understood. Recent genetic analysis has shown that disruptions of notch pathway genes cause severe vertebral defects both in mouse and humans. For example, homozygous mutations in delta-like 3, a ligand in the notch signaling pathway, are found both in the pudgy mouse, which displays vertebral defects, and in the human vertebral disorder, spondylocostal dysostosis. Under the overall goal of understanding the regulation of the somite clock, we are pursuing further genetic analysis in the following complementary areas.

First, we are working to identify novel genes involved in the segmentation clock. Certain genes in the notch signaling pathway display oscillatory changes in expression that are synchronized with somite formation. We are using microarray technology to identify novel genes with oscillatory expression in mouse embryos, and to identify genes downstream of the notch pathway signaling using targeted mouse mutants. In parallel, we are also identifying genes with oscillatory expression in human mesenchymal stem cell models of the segmentation clock.

Second, we have worked to establish the International Consortium for Vertebral Anomalies and Scoliosis, a group of geneticists and orthopaedic surgeons interested in identifying the developmental origins of spinal birth defects. Our collaborative aim is to identify the genetic etiology of human vertebral disorders, including congenital scoliosis, Klippel-Feil syndrome, Jarcho-Levin syndrome, and caudal agenesis. We have developed a unique clinical database of congenital vertebral defect cases for molecular analysis, to aid us in our goal of finding the genetic and developmental causes of spinal birth defects.

Selected Publications

Loomes KM, O'Brien ML, Stevens SA, Sewell W, Ryan M, Dormans N, Schaffer AA, Mimoto MS, Nah H-D, Pratt SC, Dunwoodie SL, Kusumi K. Dll3-Notch1 mutant mice are a model for congenital scoliosis and craniofacial defects. Dev Dynam, in press.

Turnpenny PD, Alman B, Cornier AS, Giampietro PF, Offiah A, Tassy O, Kusumi K, Dunwoodie SL. Abnormal vertebral segmentation and the notch signaling pathway in man, Dev Dynam, 2007;236:1456-1474.

William DA, Saitta B, Gibson JD, Traas J, Markov V, Gonzalez DM, Sewell W, Anderson DM, Pratt SC, Rappaport E, Kusumi K. Identification of oscillatory genes in somitogenesis from functional genomic analysis of a human mesenchymal stem cell model. Dev Biol, 2007 May 1;305(1):172-186.

Markov V*, Kusumi K* (joint 1st authors), Tadesse M, William DA, Gonzalez DM, Lounev V, Carlton A, Leonard J, Cohen RI, Rappaport RF, Saitta B. Identification of distinct cord blood-derived mesenchymal stem/stromal cells with different growth kinetics, differentiation potentials, and gene expression profiles. Stem Cells Dev, 2007 Feb;16(1):53-73.

Kusumi K, Turnpenny PD. Formation errors of the vertebral column. J Bone Joint Surg Am . 2007 Feb;89 Suppl 1:64-71

Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet, 2006 Jan;78(1):28-37.

Schaffer AA, Kaplan FS, Tracy MR, O'Brien ML, Dormans JP, Shore EM, Harland RM, Kusumi K. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome: clues from the BMP signaling pathway. Spine. 2005 Jun 15;30(12):1379-85.

Maisenbacher MK, Han JS, O'Brien ML, Tracy MR, Erol B, Schaffer AA, Dormans JP, Zackai EH, Kusumi K. Molecular analysis of congenital scoliosis: a candidate gene approach. Hum Genet. 2005 Apr;116(5):416-419

Erol B, Tracy MR, Dormans JP, Zackai EH, Maisenbacher MK, O’Brien ML, Turnpenny PD, Kusumi K. Congenital Scoliosis and Vertebral Malformations: Characterization of Segmental Defects for Genetic Analysis. J Pediatr Orthop. 2004 Nov-Dec;24(6):674-682.

Kusumi K, Mimoto MS, Covello K, Beddington RSP, Krumlauf R, Dunwoodie SL. The Dll3 pudgy mutation differentially disrupts dynamic expression of somite genes. Genesis, 2004 Jun;39(2):115-21.

Kusumi K, Dunwoodie SL, Krumlauf R. Dynamic expression patterns of the pudgy/spondylocostal dysostosis gene Dll3 in the developing nervous system. Mech Dev. 2001 Jan;100(1):141-4.

Bulman MP*, Kusumi K* (*contributed equally), Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet. 2000 Apr;24(4):438-41.