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.
Highlights
The developing kidneys undergo complex morphogenesis to become fully functional, non-regenerating organs at birth
It has become evident that receptor tyrosine kinase (RTK)-activated signaling is a key regulator of kidney development [1,2]
The significant roles of the MAPK/ERK pathway in morphogenesis are emerging [5,6,7,8], and we recently reported the activation of MAPK/ERK patterns and functions in nephron progenitors (NPs) of the developing kidney [9]
Summary
The developing kidneys undergo complex morphogenesis to become fully functional, non-regenerating organs at birth. Renal morphogenesis is guided by classical inductive interactions, which are known to take place through cell-cell-induced signaling, leading to activation of cell-intrinsic intracellular cascades. The major inducers of RTK signaling in the early developing kidney include glial cell line-derived neurotrophic factor (GDNF)-induced RET signaling and fibroblast growth factor (FGF) signaling. Binding of these growth factors to their cognate receptors causes receptor dimerization, autophosphorylation, and activation of intracellular signaling cascades, including the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway [3,4]. RTK signaling h1.a1.sRiTmK Spigonratlianng itnfGuennecratlions in regulating cellular processes such as cell cycle progression during proliferatioTnhe, RcTeKlslfomrmeatafabmoillyisomf ce,ll-msurifgacrearteicoepnto, rsspuorsvseisvsiangl,anaenxdtracdelilufflaerrdeonmtaiianttihoant b.indSs everal growth factors (e.g., eptRoiTdsKiegsnrigamnlianalgilnmggohrlaeoscwuimletpshosrutfacahntcaftsuongrcr,otiwoinnthssifnuacrlteiognrus,,lahationnrgmdcoenltlehusl,eacryiptnoroksciuneselssie,nsa-snuldickhneeausrgcoertlrloocpwyhciltcehpfarcfotagorcrestso[s1iro0)n]. bind to RTKs, upon which thedtuyrirnogspirnoeliferreastiiodnu, ceelsl mwetiatbhoilnismth, meigrreactieopn,tsourrvsivaarl,eanpdhdoifsfeprehnotiratyiolna.tSeedve,rlael agrdowinthgfatcotocrshanges in either downstream tar(eg.ge.,tepgiedenremaelxgrporwethssfaicotonr ,ainnsdul/ion,rancdytthoesinosluilcinp-lirkoe tgeroiwnthpfhacotosrp) bhinodrtyolRaTtKios,nup[o1n1w].hiTchhe intracellular pathways meditdahotewinntygsrtoreesaxinmtertaarecrsgeiedltlugueeslnaewreixsthptiirnemsstuhioelniraienncdet/pootrotrchsyteoarsceoelipcllhpoirnsoptteheionrriypolharotesidpn,hcollreuyalddaitneiog,nft[oo11r]c.heTaxhnaegmeins tprianlceee,lliutPhlIae3rr K/AKT/mTOR, RAS/RAF/MEKp/EatRhwKay, samneddiaPtiLngCeγxt/rPacKellCula[r1s2tim,1u3li]in(tFoitgheucreell i1n)te.rior include, for example, PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, and PLCγ/PKC [12,13] (Figure 1)
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