John Cobb

Embryonic development depends on the precise spatial and temporal regulation of gene expression by transcription factor proteins. Understanding how transcription factors influence cell fate decisions and subsequent morphogenesis is a fundamental question of developmental biology.  We use limb development in the laboratory mouse as a model system to study how transcription factors control the development of specific structures.  Many transcription factors that are required to form limb elements have been identified, but we know comparatively little about how these proteins actually function.  Most notably, very few of the target genes that are regulated by transcription factors during limb development have been identified.  Likewise, we know little about how the expression of the transcription factor genes themselves is controlled.  

To address these issues, my research program focuses on the mouse short-stature homeobox-containing gene 2 (Shox2), which we have shown is absolutely required for the development of the proximal bones of the limbs, the humerus and femur.  Short-stature genes are of particular interest because mutations of the human SHOX gene cause the limb deformities found in three human syndromes.  Interestingly Shox2 is the only short-stature gene in the mouse genome, while humans have two. The lack of the Shox gene in the mouse genome is especially noteworthy since virtually all other human genes involved in patterning basic embryonic structures have a single matching ortholog in the mouse.  The Shox genes therefore present a unique opportunity to study how very similar structures (i.e. human and mouse limbs) can be patterned by different gene complements.

• Google Scholar Link
• Jessica M Rosin, Deborah M Kurrasch and John Cobb. (2015) Shox2 is required for the proper development of the facial motor nucleus and the establishment of the facial nerves. BMC Neuroscience. 16:39 doi:10.1186/s12868-015-0176-0.
• Rosin, Jessica M.; McAllister Brendan B; Dyck, Richard H.; Percival, Christopher J,; Kurrasch Deborah, M.; Cobb, John. (2014) Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination. Developmental Biology. doi: 10.1016/j.yd- bio.2014.12.013.
• Rosin, J.M.; Abassah-Oppong, S.; Cobb, J. (2013) Comparative transgenic analysis of enhancers from the human SHOX and mouse Shox2 genomic regions. Human Molecular Genetics. Epub ahead of print, doi: 10.1093/hmg/ddt163.
• Bobick, B.E.; Cobb, J. (2012) Shox2 regulates progression through chondrogenesis in the mouse proximal limb. Journal of Cell Science. 125: 6071-6083. 
• Neufeld S.; Rosin J.M.; Ambasta A.; Hui K.; Shaneman V.; Crowder R.; Vickerman L.; Cobb J. (2012) A conditional allele of Rspo3 reveals redundant function of R-spondins during mouse limb development. Genesis. 50: 741-749. 
• Scott, A.; Hasegawa, H.; Sakurai, K.; Yaron, A.; Cobb, J.; Wang, F. (2011) Transcription factor short stature homeobox 2 is required for proper development of tropomyosin-related kinase B-expressing mechanosensory neurons. Journal of Neuroscience. 31: 6741-6749. 
• Vickerman L, Neufeld S, Cobb J. (2010) Shox2 function couples neural, muscular and skeletal development in the proximal forelimb. Dev Biol. 2011 Feb 15;350(2):323-36. Epub 2010 Dec 13.
• Cobb, J.; Dierich, A.; Huss-Garcia, Y.; Duboule D.  (2006) A mouse model for human short stature syndromes identifies Shox2 as an upstream regulator of Runx2 during long bone development. Proceedings of the National Academy of Sciences, USA 103: 4511-4515.
• Cobb, J.; Duboule, D. (2005) Comparative analysis of genes downstream of the Hoxd cluster in developing digits and external genitalia.  Development 132: 3055-67.  
• Eaker, S.; Cobb, J.; Pyle, A.; Handel, M. A. (2002) Meiotic prophase abnormalities and metaphase cell death in MLH1-deficient mouse spermatocytes: insights into regulation of spermatogenic progress. Developmental Biology 249: 85-95. 
• Libby, B. J.; De La Fuente, R.; O'Brien, M. J.; Wigglesworth, K.; Cobb, J., Inselman, A.; Eaker, S.; Handel, M. A.; Eppig, J. J.; Schimenti, J. C. (2002) The mouse meiotic mutation mei1 disrupts chromosome synapsis with sexually dimorphic consequences for meiotic progression. Developmental Biology 242: 174-87. 
• Eaker, S.; Pyle, A.; Cobb, J.; Handel, M. A. (2001) Evidence for meiotic spindle checkpoint from analysis of spermatocytes from Robertsonian-chromosome heterozygous mice. Journal of  Cell Science 114: 2953-65

• Courses