Table 1.
Phenotypes of mouse models with Notch signaling activity modulated within the developing kidney.
| Regulatory Region Driving Cre/Time Point and Place in Renal System Where Inactivation Occurs | Mouse Model: Genetically Modified Gene and Observed Phenotype | Reference |
|---|---|---|
| Hypomorphic Notch2 alleles (Notch2 del1/del1) | Notch2 del1/del1: Perinatal lethality with hypoplastic kidneys, vascular lesions near cortical region, defective glomerulogenesis, and lack of proper glomeruli | [32] |
| Notch 2 +/del1, Jag1 +/−: Half sized kidneys, decrease in glomeruli number, defective glomeruli | ||
| Notch 2 +/del1, Dll1 +/−: No kidney defects | ||
| Global deletions and global overexpression | Psen1 −/−, Psen2 −/− with rescue of severe pre-natal lethality by PSEN1 human expression: Lethality at 2 h post birth, smaller kidneys that lack comma and S-shaped bodies, glomeruli, proximal tubules, and distal nephron tubule begins formation but does not fully mature |
[34] |
| Hoxb7->Cre/collecting duct | Human Jag1 gene overexpression: Variable phenotypes including cysts, decreased nephrons, hypoplastic kidneys, hydropelvises, hydroureters along with drastically lowered GDNF expression levels | [26] |
| Pax3->Cre/Metanephrogenic Mesenchyme Pre-11.5 | Notch2 f/f: Lethality between P1 and P2 due to renal failure with no filtration apparatus present, smaller kidneys with collapsed renal pelvis, no proximal tubules with intact distal tubules, and lack of proximal podocytes | [40] |
| Pax2-Cre/Pre-10.5 renal development | Notch2 f/f: No podocytes or proximal tubules present in kidneys of mutants | |
| RBPJ f/f: Death by E13.5, explant culture revealed lack of proximal tubule and podocytes Notch1f/f: Explant kidney shows no phenotype | ||
| Six2->GFP-Cre/E12.5 onwards in cap mesenchyme | NICD overexpression: Hypoplastic kidneys with only one ureteric branch | |
| Neph->Cre/Podocytes only | NICD overexpression: Proteinuria caused by impaired glomerular filtration selective permeability with progressive glomerulosclerosis and a decrease in mature marker expression (Wt1, Nphs1, and Nphs2) with increased cell cycle activity and increased Pax2 expression | [47] |
| Podocin->Cre/Podocytes only | RBPJ f/−: No observable phenotype | |
| RBPJ f/−, NICD overexpression: Rescue of severe selective filtration defect from increased Notch and rescue of Glomerulosclerosis | ||
| Hoxb7->Cre/collecting duct | Mib1 f/f: Unilateral or bilateral hydronephrosis of distended kidneys at P17, reduced number of principal cells, and increased number of intercalated cells | [36] |
| Six2->GFP-Cre/E12.5 onwards in cap mesenchyme surrounding ureteric bud tips | N2-ICD overexpression: Lethality after birth and kidneys have glomerular cysts, dilated renal tubules, and thin cortexes | [45] |
| Six2->GFP-Cre/E12.5 onwards in cap mesenchyme surrounding ureteric bud tips | Notch2 f/f: Low percentage of renal cysts at P0 with a formation of micro adenomas (proliferating cells) by 52 weeks of age | [48] |
| Notch1 f/f: 30% of mutant mice have renal cysts at P0 | ||
| RBPJ f/f: Lethality by P2 in mutants, kidneys have few glomeruli and proximal tubules | ||
| Rarb2->Cre/Condensing mesenchyme | RBPJ f/f: Large proximal tubule cysts present in mutant kidneys | |
| Six2->GFP-Cre/E12.5 onwards in cap mesenchyme surrounding ureteric bud tips | Notch2 f/f: 31% of mutants have smaller kidneys with fewer glomeruli | [42] |
| Notch1 +/f; Notch2f/f: 67% of mutants have smaller kidneys with fewer glomeruli, increased blood urea nitrogen levels at birth, reduced life span | ||
| Notch1 f/f, Notch2 f/f: Lethality at P1 with compromised renal function (blood urea nitrogen), few proximal tubules with very few glomeruli | ||
| RBPJ f/f: Mutants mice die at P2 due to insufficient filtration in small kidneys Kidneys have few mature nephrons and no S-Shaped body during development with few proximal tubules | ||
| Pax3->Cre/Metanephric Mesenchyme Pre-11.5 | Notch2 f/f, Mint f/f: Mint inactivation partially rescues Notch2-deficient phenotype by increasing the number of proximal nephron segments forms | |
| Rarb2->Cre/Condensing mesenchyme | RBPJ f/deletion: Hypoplastic kidneys that develop cysts with death due to increased blood urea levels causing renal failure Fewer proximal tubules formed, were dilated and cyst-like, with few glomeruli that were functioning Note: Some progenitors escape RBPJ inactivation leading to the development of the present proximal tubules |
[49] |
| Hoxb7->Cre/Collecting duct | Adam10 f/f: Hydronephrosis in 30% of mutants with increased water intake, increase urine output, and decreased osmolality; decrease in principal cells and an increase in intercalated cells in collecting duct | [37] |
| Six2->GFP-Cre/ E12.5 onwards in cap mesenchyme surrounding ureteric bud tips |
Six2-3XFlag overexpression: Decreased differentiation from mesenchymal progenitors to epithelial tubules | [25] |
| RBPJ f/f: Increased Six2+ cells found deeper in medullary, decreased nephron endowment | ||
| N1 f/f, N2 f/f: Increased Six2+ cells found deeper in medullary, decrease in the number nephrons, lack of development of proper nephrons, and renal vesicles failed to form S-shaped bodies Important note: Mosaicism in Cre positive cells formed some nephrons | ||
| Hoxb7-Cre/Collecting duct | Rbpj f/−: Increased intercalated cells in collecting duct, decreased expression of Elf5 | [50] |
| PS1 −/f and Ps2 −/−: Increased intercalated cell gene expression with decreased principal cell gene expression | ||
| Rosa +/NICD: Increased principal cell gene expression including Elf5 | ||
| Cdh16->Cre/Collecting duct and connecting tubule | Elf5 F/del: Slight decrease in principal cell gene expression | |
| Wnt4->GFP-Cre/Pre-tubular aggregates | Notch1 f/f, Notch2 f/f: Lack of developed nephrons and not just proximal tubules as previously noted, no premature depletion of mesenchymal nephron progenitors | [51] |
| NICD overexpression: No effect on nephron differentiation, glomerulocystic kidney phenotype | ||
| Six2->GFP-Cre/E12.5 onwards in cap mesenchyme surrounding ureteric bud tips | Rosa LacZ/NICD: Glomerulocystic kidneys within mutants; heterogeneous nephron cell population segmenting in the nephron, and not just proximal tubule population as previously found | |
| Cdh16->Cre/Collecting duct and connecting tubule | Jag1 f/f: Increase in collecting duct cell types expressing both principal and intercalated proteins with tubules enlarged as well as enclosing fragments of the tubule; hydronephrosis present in adult mice | [52] |
| Tfcp2l1 f/f: Absence of intercalated cell development in collecting ducts | ||
| Atp6v1b1->Cre/Intercalated cells of the collecting duct (possibly leaky expression in principal cells) |
Jag1 f/f: Increase in cells expressing both principal and intercalated proteins within the collecting duct with decreased principal cells | |
| Tfcp2l1 f/f: Standard ratio of principal to intercalated cells in collecting duct at two weeks of age; by two months the collecting duct contains half of the intercalated cells with decreased intercalated protein expression when compared to wild-type | ||
| EllA-Cre/ Early embryogenesis; one cell zygote stage |
Tfcp2l1 f/f: Lethality post birth; elimination of intercalated cells in collecting duct |