Urogenital System Development: The Acquisition of Coordinated Ureter Peristalsis
Principal Investigator: Doris A Herzlinger
Abstract: DESCRIPTION (provided by applicant): Coordinated contractions of the smooth muscle coat surrounding the kidney outflow tract (OT), including the renal calyces, pelvis and ureter, are essential for draining urine out of the kidney. Congenital defects that impair this peristaltic process are common, and the leading cause of renal failure in children. However, the signaling pathways that control the differentiation of the cell types mediating urinary tract peristalsis remain poorly understood. In the previous funding period we showed that Bone Morphogenetic Protein signaling during the early stages of development is essential for the formation of the OT smooth muscle coat. In this project we will study the differentiated cell types that coordinate contraction in this musculature. We recently discovered that the normal initiation and coordination of OT smooth muscle contraction is dependent on Hyperpolarizing Cation Channel (HCN) activity. In Aim 1, we will determine if HCN expressing OT cells exhibit the electrophysiological and structural properties required for triggering smooth muscle contraction using our recently developed high resolution video-microscopic and optical mapping protocols and electron-microscopic techniques. Moreover, we will determine if HCN channel activity is essential for the efficient flow of urine from the kidney to the bladder by analyzing OT structure, smooth muscle contractile and electrical activity in mice with targeted HCN gene deletions. We have also uncovered a role for the tyrosine kinase receptor C-kit in controlling OT contractile activity. In Aim 2 we will analyze OT architecture and smooth muscle function in mice with loss-of-function mutant C-Kit alleles using morphological and functional assays. Aim 3 is based on our preliminary data demonstrating that mice harboring a constitutively active C-kit allele develop fetal hydronephrosis. We will determine if this defect due to C-kit gain-of-function is caused by a structural occlusion of the OT tract or as we predict, a defect in coordinated peristalsis. Collectively, the results of proposed experiments identifying the cell types required for triggering coordinated OT peristalsis will open up a new area of investigation focused on the signaling pathways controlling the differentiation of these pacemaker cells. Ultimately, our studies will reveal drug targets for the modification of ureter peristalsis and may reveal unappreciated causes of hydronephrosis.
Funding Period: 1991-09-15 - 2016-07-31
more information: NIH RePORT
- Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signalingAndrea Brenner-Anantharam
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA
Development 134:1967-75. 2007....
- Paraxial mesoderm contributes stromal cells to the developing kidneyRichard Guillaume
Weill Medical College of Cornell University, Department of Physiology and Biophysics, 1300 York Ave, New York, NY 10065, USA
Dev Biol 329:169-75. 2009..In addition, these fate mapping data indicate that renal development, like the development of all other tubular organs, is dependent on the integration of progenitors from different embryonic tissues into a single rudiment...
- The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsisRomulo Hurtado
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA
Kidney Int 77:500-8. 2010..This provides insight into the genetic causes of common inherited urinary tract disorders such as reflux and obstruction...
- Upper urinary tract pacemaker cells join the GLI clubDoris Herzlinger
Department of Physiology and Biophysics, Cornell University Medical College, New York, New York 10021 4805, USA
J Clin Invest 121:836-8. 2011..These results link defective pacemaker cell differentiation with hydronephrosis and provide a cellular basis for one of the abnormal renal defects observed in humans with the GLI3-linked disease Pallister-Hall syndrome...
- A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca2+ channelsRomulo Hurtado
1Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA
FASEB J 28:730-9. 2014..Hurtado, R., Bub, G., Herzlinger, D. A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca(2+) channels. ..
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