Research Description
Research Summary
What are the molecular pathways that dictate cardiac morphogenesis? What is the genetic and developmental basis of Congenital Heart Disease (CHD), the number one birth defect world-wide? How did the cardiovascular system evolve into a form that can support terrestrial life? These intertwined questions form the basis for the investigations underway in the Moskowitz laboratory.
Gene Discovery for CHD
We performed a gene discovery program using a forward genetic screen in mice to identify CHD-causing mutations (Kamp et al., 2010). Our initial work was the first to link cilia signaling to heart development (Friedand-Little et al., 2011). We have recently identified the CHD-causing mutations in multiple lines and are studying their effects on cardiac morphogenesis. This work has led us to the importance of gene regulatory networks in the Second Heart Field for atrial septation.
Cardiac Progenitor Specification and Cardiac Morphogenesis
Our recent work (Hoffmann et al., 2009 and Xie et al., 2012) suggests that the molecular logic governing cardiac septation is firmly established within cardiac progenitors long before septum morphogenesis occurs. In current studies we are using genomic techniques to uncover the molecular programs required in cardiac progenitors for septum morphogenesis.
Cardiac Conduction System
The Cardiac Conduction System (CCS) is a specialized network of cardiomyocytes responsible for coordinating the rhythmic contraction of the heart. We have generated novel transgenic mouse lines for CCS-specific studies (Arnolds and Moskowitz, 2011) and used them to identify a molecular pathway required for adult CCS function (Arnolds et al., 2012). We are continuing these studies to unveil the molecular logic underlying CCS function.
Summary
Our laboratory studies basic questions in cardiac development and function. We take biochemical, molecular, genetic, genomic and cellular approaches to these problems. Our aims are to elucidate general principles of organ morphogenesis using the heart as a model, understand the ontogeny of Congenital Heart Disease, and contribute to our understanding of cardiac evolution. For more information, contact Ivan at imoskowitz@uchicago.edu.
Selected Publications
A common genetic variant within SCN10A modulates cardiac SCN5A expression. van den Boogaard M, Smemo S, Burnicka-Turek O, Arnolds DE, van de Werken HJ, Klous P, McKean D, Muehlschlegel JD, Moosmann J, Toka O, Yang XH, Koopmann TT, Adriaens ME, Bezzina CR, de Laat W, Seidman C, Seidman JG, Christoffels VM, Nobrega MA, Barnett P, Moskowitz IP (2014 Mar) J Clin Invest. 2014 Mar 18. pii: 73140. doi: 10.1172/JCI73140. 24642470
Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Xie L, Hoffmann AD, Burnicka-Turek O, Friedland-Little JM, Zhang K, Moskowitz IP (2012 Aug) Dev Cell. 2012 Aug 14;23(2):280-91. doi: 10.1016/j.devcel.2012.06.006. 22898775 ( Full Text )
Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation.
Zhou L, Liu J, Xiang M, Olson P, Guzzetta A, Zhang K, Moskowitz IP, Xie L
(2017 Feb) Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1422-E1431. doi: 10.1073/pnas.1605137114. Epub 2017 Feb 6. 28167794
A common genetic variant within SCN10A modulates cardiac SCN5A expression.
van den Boogaard M, Smemo S, Burnicka-Turek O, Arnolds DE, van de Werken HJ, Klous P, McKean D, Muehlschlegel JD, Moosmann J, Toka O, Yang XH, Koopmann TT, Adriaens ME, Bezzina CR, de Laat W, Seidman C, Seidman JG, Christoffels VM, Nobrega MA, Barnett P, Moskowitz IP
(2014 Apr) J Clin Invest. 2014 Apr;124(4):1844-52. doi: 10.1172/JCI73140. Epub 2014 Mar 18. 24642470 (Full Text)
Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation.
Xie L, Hoffmann AD, Burnicka-Turek O, Friedland-Little JM, Zhang K, Moskowitz IP
(2012 Aug) Dev Cell. 2012 Aug 14;23(2):280-91. doi: 10.1016/j.devcel.2012.06.006.22898775 (Full Text)
TBX5 drives Scn5a expression to regulate cardiac conduction system function.
Arnolds DE, Liu F, Fahrenbach JP, Kim GH, Schillinger KJ, Smemo S, McNally EM, Nobrega MA, Patel VV, Moskowitz IP
(2012 Jul) J Clin Invest. 2012 Jul;122(7):2509-18. doi: 10.1172/JCI62617. Epub 2012 Jun 25. 22728936 (Full Text)
Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease.
Smemo S, Campos LC, Moskowitz IP, Krieger JE, Pereira AC, Nobrega MA
(2012 Jul) Hum Mol Genet. 2012 Jul 15;21(14):3255-63. doi: 10.1093/hmg/dds165. Epub 2012 Apr 27. 22543974 (Full Text)
Inducible recombination in the cardiac conduction system of minK: CreERT(2) BAC transgenic mice.
Arnolds DE, Moskowitz IP
(2011 Nov) Genesis. 2011 Nov;49(11):878-84. doi: 10.1002/dvg.20759. Epub 2011 Aug 24. 21504046
A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus.
Friedland-Little JM, Hoffmann AD, Ocbina PJ, Peterson MA, Bosman JD, Chen Y, Cheng SY, Anderson KV, Moskowitz IP
(2011 Oct) Hum Mol Genet. 2011 Oct 1;20(19):3725-37. doi: 10.1093/hmg/ddr241. Epub 2011 Jun 8. 21653639 (Full Text)
The emerging genetic landscape underlying cardiac conduction system function.
Arnolds DE, Chu A, McNally EM, Nobrega MA, Moskowitz IP
(2011 Jun) Birth Defects Res A Clin Mol Teratol. 2011 Jun;91(6):578-85. doi: 10.1002/bdra.20800. Epub 2011 Apr 28. 21538814 (Full Text)
Complex interactions between genes controlling trafficking in primary cilia.
Ocbina PJ, Eggenschwiler JT, Moskowitz I, Anderson KV
(2011 Jun) Nat Genet. 2011 Jun;43(6):547-53. doi: 10.1038/ng.832. Epub 2011 May 8. 21552265 (Full Text)
Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected]
Moskowitz IP, Wang J, Peterson MA, Pu WT, Mackinnon AC, Oxburgh L, Chu GC, Sarkar M, Berul C, Smoot L, Robertson EJ, Schwartz R, Seidman JG, Seidman CE
(2011 Mar) Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4006-11. doi: 10.1073/pnas.1019025108. Epub 2011 Feb 17. 21330551 (Full Text)
Genome-wide identification of mouse congenital heart disease loci.
Kamp A, Peterson MA, Svenson KL, Bjork BC, Hentges KE, Rajapaksha TW, Moran J, Justice MJ, Seidman JG, Seidman CE, Moskowitz IP, Beier DR
(2010 Aug) Hum Mol Genet. 2010 Aug 15;19(16):3105-13. doi: 10.1093/hmg/ddq211. Epub 2010 May 28. 20511334 (Full Text)
sonic hedgehog is required in pulmonary endoderm for atrial septation.
Hoffmann AD, Peterson MA, Friedland-Little JM, Anderson SA, Moskowitz IP
(2009 May) Development. 2009 May;136(10):1761-70. doi: 10.1242/dev.034157. Epub 2009 Apr 15. 19369393 (Full Text)
E2F3 plays an essential role in cardiac development and function.
King JC, Moskowitz IP, Burgon PG, Ahmad F, Stone JR, Seidman JG, Lees JA
(2008 Dec) Cell Cycle. 2008 Dec;7(23):3775-80. Epub 2008 Dec 22. 19029823(Full Text)
A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development.
Moskowitz IP, Kim JB, Moore ML, Wolf CM, Peterson MA, Shendure J, Nobrega MA, Yokota Y, Berul C, Izumo S, Seidman JG, Seidman CE
(2007 Jun) Cell. 2007 Jun 29;129(7):1365-76. 17604724
Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia.
Wolf CM, Moskowitz IP, Arno S, Branco DM, Semsarian C, Bernstein SA, Peterson M, Maida M, Morley GE, Fishman G, Berul CI, Seidman CE, Seidman JG
(2005 Dec) Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18123-8. Epub 2005 Dec 6. 16332958 (Full Text)
The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system.
Moskowitz IP, Pizard A, Patel VV, Bruneau BG, Kim JB, Kupershmidt S, Roden D, Berul CI, Seidman CE, Seidman JG
(2004 Aug) Development. 2004 Aug;131(16):4107-16. 15289437