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Jeffrey Bush Ph.D.

Signalling control of craniofacial development and congenital disease

Jeffrey Bush Ph.D.

The lab studies basic mechanisms by which signaling between cells coordinates morphogenesis. Understanding this control has significance beyond its fundamental importance in development since birth defects are the leading cause of death for infants during the first year of life. Craniofacial anomalies are the most common class of congenital defect in humans, with three quarters of all malformations identified at birth involving craniofacial dysmorphogenesis. We utilize multiple approaches based in mouse genetics to understand fundamental signaling processes as they relate to development. In addition to targeted and conditional gene disruption in mice, we are generating mice harboring targeted point mutations that disrupt specific signal transduction pathways. By integrating these in-vivo approaches with mass spectrometry-based phospho-proteomics, cell biology and biochemistry, we seek to understand the mechanistic basis of signaling control of craniofacial development.

One ongoing project focuses on a disease called craniofrontonasal syndrome (CFNS), an X-linked congenital disorder that includes a number of craniofacial, skeletal, and neurological malformations and is caused by mutations in the ephrin-B1 gene. Mice with mutations in the ephrin-B1 gene display strikingly similar phenotypes to human CFNS patients, underscoring the value of the mouse as a model for studying congenital disease. Ephrin-B1 is a member of a unique family of signaling molecules that can signal by multiple distinct molecular mechanisms. By using gene targeting in ES cells to generate mice harboring a series of signaling mutations in ephrin-B1, we learned that distinct CFNS malformations are controlled by different signal transduction pathways.

We have also integrated a mass spectrometry-based phospho-proteomic approach to identify signal transduction components of the Eph/ephrin signaling pathway in craniofacial development. The signaling network by which Eph/ephrin signaling controls craniofacial development is a topic of ongoing study in the lab.

Selected Publications:

Bush, J.O. and Soriano, P (2012) Eph/ephrin signaling: Genetic, phosphoproteomic, and transcriptomic approaches. Seminars in cell & developmental biology, 2011.

Bush, J.O.* and R. Jiang, R.(2011) Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development, 2012. 139(2): p. 231-43.

Bush, J. O. and Soriano, P. (2010). Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries. Genes Dev. 24, 2048-60.

Bush, J. O. and Soriano, P. (2009). Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Genes Dev 23, 1586-99. COVER IMAGE. Davy, A., Bush, J. O. and Soriano, P. (2006). Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol 4, e315.

Bush, J. O., Lan, Y. and Jiang, R. (2004). The cleft lip and palate defects in Dancer mutant mice result from gain of function of the Tbx10 gene. Proc Natl Acad Sci U S A 101, 7022-7. ..