MAPK/ERK Signaling in Regulation of Renal Differentiation

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects derived from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. Here we discuss advances in the understanding of how mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity contributes to the regulation of ureteric bud branching morphogenesis, which dictates the final size, shape, and nephron number of the kidney. Recent studies also demonstrate that the MAPK/ERK pathway is directly involved in nephrogenesis, regulating both the maintenance and differentiation of the nephrogenic mesenchyme. Interestingly, aberrant MAPK/ERK signaling is linked to many cancers, and recent studies suggest it also plays a role in the most common pediatric renal cancer, Wilms' tumor.

Keywords: MAPK/ERK signaling; differentiation; extracellular signal-regulated kinase; intracellular signaling; kidney development; nephrogenesis; progenitor cells; self-renewal; ureteric bud branching morphogenesis.

Figure 1

Schematic summary of the multiple MAPK pathways. MAPK pathways, highlighted in the light blue box, mediate extracellular information to the cell interior. Ligand (purple oval) binding to the dimeric transmembrane tyrosine kinase receptor (blue blocks) and/or cellular stress (inflammation, ischemia, hypoxia) activate a spectrum of downstream intracellular cascades such as PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, and PLCγ/PKC. The last step of MAPK/ERK cascade activation results in phosphorylation of ERK1/2 leading to both transcriptional target regulation in the nucleus (light lilac oval, including c-FOS, c-JUN and Cyclin D1) and in the cytoplasm (peach-colored box, including those identified in the developing kidney: E-cadherin, Paxillin, and PAX2/ITGA8) followed by cell-type specific cellular responses (green box). Black lines indicate linear activation by phosphorylation, black dotted line indicates activation within the cascade and red dotted line indicates activation by cellular stress. Abbreviations: PI3K; Phosphoinositide 3-kinases, AKT; protein kinase B, mTOR; mammalian target of rapamycin, MAP3K; MAP kinase kinase kinase, MAP2K; MAP kinase kinase, MAPK; MAP kinase, MLKs; Mixed lineage kinases, MKK; Mitogen-activated protein kinase kinase, CDC42; Cell division control protein 42 homolog, TAK1; Mitogen-activated protein kinase kinase kinase 7, MTK1; Mitogen-activated protein kinase kinase kinase 4, PLCγ; Phospholipase C gamma, PKC; Protein kinase C, pERK1/2; phosphorylated ERK1/2, Ecad; E-cadherin, PAX2; paired box protein 2, ITGA8; integrin alpha 8.

Figure 2

Induction of permanent kidney development in mice. (A) The most prominent kidney at embryonic day 10.5 (E10.5) is the mesonephros, which is a transient, embryonic kidney. At the initiation of permanent kidney development, the metanephric mesenchymal (MM, pink) cells interact with the ureteric bud (UB, yellow), and signal propagation between the MM and UB induces UB outgrowth from the nephric duct (ND) near the cloaca (C); (B) In the next step at E11.0, the MM secretes signals that attract the UB to grow towards it. The UB itself is divided into UB tip (dark brown) and trunk (yellow); (C) The first branching event takes place at E11.5 when reciprocal inductive interactions between the UB and MM lead to formation of a T-shaped UB. The previous kidney, mesonephros, begins to regress. C; cloaca, ND; nephric duct, MM; metanephric mesenchyme, UB; ureteric bud.

Figure 3

Ureteric bud (UB) branching morphogenesis. (A) Branching morphogenesis begins by the formation of a T-bud, which is composed of the UB trunk (yellow) and tips (dark brown). At this stage, the metanephric mesenchyme is condensed around the UB tips and forms cap mesenchyme (CM, light red). UB-derived signals induce CM cells to undergo mesenchyme-to-epithelial (MET) conversion and produce the renal vesicle (RV, purple) in the armpits of the T-bud; (B) By E12.5, the UB has undergone a series of iterative branching events under the influence of mesenchymal signals. Most of the UB branches form by stereotypic bifurcation of an existing tip, and each new tip maintains the surrounding CM. The UB undergoes a total of approximately 10 to 11 rounds of branching events during which it induces MET and thus nephrogenesis within each newly generated tip. CM; cap mesenchyme, UB; ureteric bud, Tip; UB tips, RV; renal vesicle.