Faculty

Maija Zile, Professor

Postdoctoral Fellow, Harvard University, 1959-61
Postdoctoral Fellow, University of Wisconsin at Madison, 1959
Ph.D., University of Wisconsin, 1959
M.S., University of Wisconsin, 1956

208A G.M. Trout FSHN Building
Michigan State University
East Lansing, MI 48824-1224
Phone: (517) 355-8474, Ext. 127
Lab: (517) 355-8474, Ext. 163
Fax: (517) 353-8963
E-mail: zile@msu.edu

Research Interests: 

The research in our  laboratory focuses on the molecular  function of  the  vitamin A active  form, retinoic acid, during  early embryonic  cardiovascular  development. Vitamin A is essential for all physiological functions throughout the life cycle; its presence is especially critical during embryonic development, as insufficiency of vitamin A causes various embryonic/fetal abnormalities depending on the stage of development when the insufficiency is inflicted. The completely vitamin A-deficient avian embryo is grossly abnormal; major abnormalities include the cardiovascular system; these  embryos die at day 3.5 of embryonic life. This is particularly relevant since congenital heart defects in the Western industrialized world are as high as 12 per 1000 live births and represent about 10 percent of all congenital malformations. Pediatric cardiovascular abnormalities account for 8 percent of all congenital malformations at birth. The etiology of these birth defects is largely unknown. However, inadequate or inappropriate nutritional cues during early organ programming and morhogenesis are likely contributors to these birth defects. In this context it is important to remember that the vitamin A-active molecule, retinoic acid (RA), is one of the major growth regulatory molecules during development.The critical  RA-requiring developmental window in the avian embryo coincides with the first 2-3 weeks of human pregnancy and may be severely compromised if maternal vitamin A intake is marginal or if there is interference with vitamin A function during pregnancy. The high incidence of vitamin A deficiency in developing countries may be responsible for an increased incidence of congenital malformation in these populations. Understanding the molecular role of vitamin A nutrition in early-life events is of key importance to forming intervention strategies during human development so as to minimize the incidence of cardiovascular birth defects and problems arising from them in adult life. Since early cardio-vascular development is similar across species, we have developed a vitamin A-deficient quail embryo “retinoid ligand knockout” model that enables us to study the molecular  function of RA during early cardiovascular morphogenesis that can not be studied in other models. Our unique model provides an opportunity to manipulate early embryos in ovo or in culture and to address vitamin A function during cardiovascular development at the gene, cellular and morphological levels. The goal of our research is to elucidate the initially dysregulated events(s) that cause gross anomalies in cardiovascular development if the vitamin A active form, retinoic acid, is not present in the embryo at the time of the initiation of formation of the cardiovascular system. We have already  identified various developmental genes that are regulated by RA during the critical RA-requiring window, i.e. HoxB1, Msx1& 2, cardiogenic  transcription factor GATA-4, several heart asymmetry genes;  the extracellular matrix gene fibronectin, the cell-cell  adhesion molecule N-cadherin and the  global growth  regulatory genes TGFbeta 1, 2, 3 and Bmp 2.  Current research focuses on the characterization of  the mechanism(s) how RA regulates these genes in cardiovascular development and on identification of gene(s) that are direct targets of retinoic acid.

Instructional Activities:

HNF/ANS 937 – Mineral and Vitamin Nutrition and Metabolism

Team-taught with the Department of Animal Science. A biochemically oriented graduate course, covering basic concepts of the function of vitamins and minerals. Teaching the vitamins part of the course with strong emphasis on the regulatory roles of these molecules at  cellular and  molecular level , on recent research developments and on health implications.

HNF 840 – Human Nutrition and Chronic Diseases

Team-taught; dietary intervention and treatment of chronic diseases.  Teaching diet, nutrition and cancer.

Outreach Focus:

My outreach area is connected to projects in Latvia, in collaboration with the MSU international programs in agriculture and study abroad.

Recent Publications:

Romeih, M., Cakstina, I. and Zile, M.H. Retinoic acid is a negative physiological regulator of N-cadherin function during avian heart morphogenesis. Dev. Growth & Differ. (in press)

Vilaspasa, L.F., Jansen, H.L., de Roos, K., Chandraratna, R., Zile, M.H., Stern, C.D. and Durston, A.J. Retinoid signaling is required for information transfer from mesoderm to neuroectoderm during gastrulation. (in press)

Garic-Stankovic, A., Hernandez, M., Flentke, G.R., Zile, M., and Smith, S.M. A ryanodine receptor-dependent Cai2+ asymmetry at Hensen's node mediates avian lateral identity. Development 135, 3271-3280, 2008.

Halilagic A, Ribes V, Gyselinck NB, Zile MH, Dolle P and Struder M. Retinoids control anterior and dorsal properties in the forebrain by modulating BMP and WNT signalling. Dev. Biol. 303, 362-375, 2007.

Zile, M.H. Vitamin A deficiency and excess. In: Nelsons Textbook of Pediatrics, 18th edition (Kliegman, R.M., Behrman, R.E., Jenson, H.B. and Stanton, B.G. Eds.) Ch.45.pp.242-245. Saunders/Elsevier, Philadelphia. 2007.

Zile, M.H. and Chenoweth, W. Vitamin C (Absorbic acid). In: Nelson's Textbook of Pediatrics, 18th edition. (Kliegman, R.M., Behrman, R.E., Jenson, H.B. and Stanton, B.F. Eds.) Ch. 47, pp.251-253. Sounders/Elsevier, Philadelphia. 2007.

Ghatpande S, Brand T, Zile MH and Evans T. "Bmp2 and GATA-4 function additively to rescue heart tube development in the absence of retinoids." Dev. Dyn. 235;2030-2039, 2006.

Kil S-H, Streit A, Brown SP, Agrawal N, Collazo, A, Zile MH and Groves AK. "Distinct roles for hindbrain and paraxial mesoderm in the induction and patterning of the inner ear revealed by a study of vitamin A -deficient quail." Dev. Biol. 285:252-271, 2005.

Zile MH. "Vitamin A requirement for early cardiovascular morphogenesis specification in the vertebrate embryo: insights from the avian embryo." Exptl. Biol. Med. 229:598-606, 2004.

LaRue AC, Argraves WS, Zile MH and Drake CJ. "Critical role for retinol in the  generation/differentiation of angioblasts required for embryonic blood vessel formation." Dev. Dyn. 230:666-674, 2004.

Cui J, Michaille J-J, Jiang W and Zile MH. "Retinoid  receptors and vitamin A  deficiency: differential patterns of transcription during early avian development and the rapid  induction of  RARs by retinoic acid." Dev. Biol. 260:496-511, 2003.

Romeih M, Cui J, Michaille J-J, Jiang W and Zile MH. "Function of RARγ and RARα2 at the initiation of retinoid signaling is essential for avian embryo survival and for distinct events in cardiac morphogenesis." Dev. Dyn. 228:697-708, 2003.

Halilagic A, Zile M and Studer M. "A novel role for retinoids in patterning the avian forebrain during presomite stages." Development. 130:2039-2050, 2003.

Ghatpande S, Gathpande A, Sher J, Zile MH and Evans T. "Retinoid signaling regulates primitive (yolk sac) hematopoiesis." Blood. 99:2379-2386, 2002.

Zile MH. "Function of vitamin A in vertebrate embryonic development." J. Nutr. 131:705-708, 2001.

Schlange T, Schnipkoweit I, Andrée B, Ebert A, Zile MH, Arnold H-H and Brand T. "Chick CFC controls Lefty1 expression in the embryonic midline and Nodal expression in the lateral plate." Dev. Biol. 234:376-389, 2001.

Griffith M and Zile MH. "Retinoic acid, midkine and defects of secondary neurulation."     Teratology. 62:123-133, 2000.

Ghatpande S, Ghatpande A, Zile MH and Evans T. "Anterior endoderm is sufficient to
rescue foregut apoptosis and heart tube morphogenesis in a embryo lacking retinoic acid." Dev. Biol. 219: 59-70, 2000.

Maden M, Graham A, Zile MH and Gale E. "Abnormalities of somite development in the absence of retinoic acid." Int. J. Dev. Biol. 44:151-159, 2000.

Zile MH, Kostetskii I, Yuan S, Kostetskaia E, St. Amand T, Chen Y-P. and Jiang W. "Retinoid signaling is required to complete vertebrate cardiac left-right symmetry pathway." Dev. Biol. 223:323-338, 2000.

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