Research Abstract:
Our laboratory studies the genetic determinants and molecular mechanisms of development and diseases in the kidney and in other structures.
In the excretory system, we have particular interests in the study of genetic determinants and the pathogenic mechanism of congenital urinary tract defects. We have used a variety of molecular genetic methods to create experimental and disease models to study the normal and abnormal development of the urinary tract. We have shown that calcineurin regulates the proliferation of the urinary tract smooth muscle cells critical for the peristalsis required for urine transfer. Specific inactivation of calcineurin in metanephric mesenchyme giving rise to urinary tract smooth muscle cells leads to failure in urine transfer and obstructive nephropathy. We continue to modulate the function of genes in the calcineurin/NFAT, TGFbeta/BMP, and Wnt signaling pathways in a temporally and spatially specific manner by various molecular genetic manipulations in mice to dissect the signaling circuits in normal and disease states. Besides these reverse genetics approaches, we are also using forward genetics to reveal the hereditary determinants of renal diseases. We have identified a mutation in a critical serine residue in Aquaporin 2 that disrupted its phosphorylation and subsequent polarized trafficking to the apical membrane of the renal collecting duct epithelia, causing failure in water reabsorption, polyuria, Nephrogenic Diabetes Insipidus, hydronephrosis, and renal failure. We are performing genetic mapping on other naturally occurred mutants with urinary tract defects. In another set of projects, we use various Cre transgenes to conditionally ablate specific renal cell types through the expression of a Diphtheria Toxin gene. We are using these animal models to study the roles of the targeted cells during development and in maintaining homeostasis. We are also studying the injury process and the repair mechanism in these models.
We also study the development of the heart and limbs. In the cardiovascular system, outflow tract abnormalities constitute a large portion of congenital heart defects. We are studying the molecular mechanism by which the neural crest cells interact with the mesodermal cells within the anterior/secondary heart field for the formation of the outflow tract. In addition, we are interested in the signals controlling digit formation in the limbs.
Selected Publications:
Jia Q, McDill BW, Li S-Z, Deng C, Chang C-P, Chen F. Smad signaling in the neural crest regulates cardiac outflow tract remodeling through cell autonomous and non-cell autonomous effects. Developmental Biology (In press).
Li S-Z, McDill BW, Kovach PA, Ding L, Go WY, Ho SN, Chen F. Coordinate regulation of AQP2 expression by the calcineurin-NFATc pathway and the TonEBP/NFAT5 osmotic stress response. American J Physiology Cell Physiology 2007 292:C1606-C1616. (Commentary on American J Physiology Cell Physiology 2007 292:C1581-C1582. Interplay between TonEBP and calcineurin-NFATc signaling pathways: a means of optimizing water reabsorption? Focus on "Calcineurin-NFATc signaling pathway regulates AQP2 expression in response to calcium signals and osmotic stress" by Udo Hasler)
McDill BW, Li S-Z, Kovach PA, Ding L, Chen F. Cph (congenital obstructive hydronephrosis) is caused by an S256L mutation in AQP2 that affects its phosphorylation and apical membrane incorporation. Proc Natl Acad Sci 2006 103:6952-6957.
Chang C, McDill BW, Neilson JR, Joist HE, Epstein JA, Crabtree GR, F. Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J Clinical Investigation 113:1051-1058. (Commentary on J Clinical Investigation 2004 113:957-959. Functional obstruction: the renal pelvis rules by Cathy Mendelsohn).
Schaeffer PJ, Wende AR, Magee CJ, Neilson JR, Leone TC, Chen F, and Kelly DP. Calcineurin and calcium/calmodulin dependent protein kinase activate distinct metabolic gene regulatory programs in cardiac muscle. J Biological Chem 2004 279:39593-39603.
Last Updated: 08/27/2007 |