Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT

Abstract

Islet1 (Isl1) is a transcription factor transiently expressed in a subset of heart and limb progenitors. During studies of limb development, conditional Isl1 deletion produced unexpected kidney abnormalities. Here, we studied the renal expression of Isl1 and whether it has a role in kidney development. In situ hybridization revealed Isl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditional deletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT). The absence of Isl1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The abnormal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia. Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, Isl1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud. These observations call for further studies to investigate whether Isl1 may be a causative gene for human CAKUT. The mammalian kidney, the metanephros, is formed by reciprocally inductive interactions between two precursor tissues: the metanephric mesenchyme and the ureteric bud. The metanephric mesenchyme attracts the ureteric bud tips toward the mesenchyme and subsequently induces branching of the ureteric buds. The attracted ureteric bud tips in turn induce the mesenchymal cells to differentiate into the epithelia of the glomeruli and renal tubules. Impairment of these processes can lead to a variety of abnormal developmental disorders of the kidney. Meanwhile, the stalks of the ureteric buds elongate and differentiate into collecting ducts and the ureter. The ureteric epithelium also interacts with the surrounding ureteral mesenchyme, which differentiates into the smooth muscle layer of the ureter that pushes the urine downward by peristaltic movements. Therefore, mechanical obstruction of the ureter or malformation of the smooth muscle layer causes dilatation of the ureter (hydroureter) and, in more severe cases, of the renal pelvis (hydronephrosis). The combination of kidney and ureter defects caused by gene mutations is termed congenital anomalies of the kidney and urinary tract (CAKUT) and

Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy

“…In a recent mouse study, Kaku et al induced conditional Isl1 deletion in the lateral mesoderm using a Hoxb6-Cre driver, and demonstrated that this caused kidney agenesis or hydroureter [ 35 ]. The authors observed transient Isl1 expression between E10.5—E14.5.…”

Yap and Taz are required for Ret-dependent urinary tract morphogenesis

“…Cell specification and cell polarity are not eliminated by loss of Yap in the ND Several genes have been implicated in ureter-bladder maturation, affecting either migration of the ND (Gata3, Raldh2, Ret), UB sprouting position (Gata2, Bmp4), formation of a single UB (Gata3, Ret, Slit2, Robo2, Sprouty1, Islet1; see Grieshammer et al, 2004;Basson et al, 2005;Kaku et al, 2013;Hoshi et al, 2012;Jain et al, 2006), defective CND elimination by apoptosis (Rar, Ptprs;Ptprf, RetY1015F, Dlgh1) or defective adhesion between the ND and the cloacal epithelium (EphA4, EphA7, EphrinB2; see Weiss et al, 2014). We looked at the expression of Robo2, Gata3, Sprouty1, Raldh2, Ret, Bmp4, Slit2, Islet1, EphA4, EphA7 and EphrinB2 by in situ hybridization (ISH), but did not detect any significant changes in expression between controls and Yap cKO (supplementary material Fig.…”

Expression and function of the LIM-homeodomain transcription factor Islet-1 in the developing and mature vertebrate retina

“…These domains are zinc fingers that coordinate two zinc ions and mediate proteineprotein interactions (Bhati et al, 2008). Studies of diverse vertebrate models have established that the LIM-HD factors are critical for the development of specialized cells in multiple tissue types, including the nervous system (Ericson et al, 1992;Pfaff et al, 1996;Porter et al, 1997;Moreno et al, 2008a,b,c;Deng et al, 2014), the heart (Pandur et al, 2013), the urogenital system (Kobayashi et al, 2004;Kaku et al, 2013), and such endocrine organs such as the pituitary gland (Mullen et al, 2007) and the pancreas (Ahlgren et al, 1997). In the case of the developing vertebrate central nervous system, LIM-HD transcription factors play crucial roles in controlling cell fate specification, survival and differentiation, and axonal projection patterns (Tsuchida et al, 1994;Hobert and Westphal, 2000;Bach, 2000).…”