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. 2020 Mar 24;8:183. doi: 10.3389/fcell.2020.00183

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Copyright © 2020 Khoshdel Rad, Aghdami and Moghadasali.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Crosstalk between major signaling pathways during nephron progenitor cell (NPC) differentiation. WNT9b, BMP7, and FGF2/9 are secreted by UB cells (green color). Stromal cells secret Decorin, SFRP1, Fat4, and TGFβ2 (orange color). High levels of WNT9b/β-catenin increase expression of the differentiation-specific genes (PAX8, C1qdc2, and WNT4) of nephron progenitor cells (NPCs). Fat4/Hippo signaling amplifies β-catenin activity. On the other hand, WNT signaling can be inhibited by SFRP1 and DKK1 to arrive appropriate number of nephrons in a definitive kidney. The BMP7/SMAD1/5 signaling pathway promotes differentiation of NPCs. Decorin antagonizes BMP7/SMAD signaling in NPCs. BMP7 activates proliferation by the TAK1-JNK-JUN cascade. FOS activation is regulated by FGF9. AP1 (a dimeric transcription factor composed of Jun and FOS) acts as a point of collaboration between the BMP7 and FGF9 signaling pathways. AP-1 activates transcription of a variety of genes (MYC, BCL-2, and p53) related to the cell cycle and anti-apoptotic events; thereby, it regulates survival and proliferation of NPCs. The FGF/RAS-MAPK, FGF/PI3K/AKT signaling pathway promotes survival and proliferation of NPCs. After binding of Notch2 to Notch ligands, NICD is released into the cytoplasm and translocates to the nucleus where the complex decreases self-renewal specific gene expression and primes NPCs for differentiation. TGFβ2 is required for MET-related gene expression during NPCs differentiation. AKT, protein kinase B; ALK, anaplastic lymphoma kinase; AP1, activator protein 1; APC, adenomatous polyposis coli; BMP, bone morphogenetic protein; CK1, casein kinase 1; Csl, CBF1/RBP-J, Su(H), Lag-1, the mammalian, fly, and worm orthologous proteins; DKK1, DKK1, Dickkopf-1; DVL, homologous to drosophila Dishevelled; EC, endothelial cells; ERK, extracellular signal-regulated kinase; Fat4, tumor suppressor homolog 4; FGF, fibroblast growth factor; Frz, Frizzled; GAB1, Grb2-associated binder 1; GSK-3β, glycogen synthase kinase 3β; GRB2, growth factor receptor-bound protein 2; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LATS1, large tumor suppressor homolog 1; LEF, lymphoid enhancing factor; LRP, low-density lipoprotein receptor-related protein; MAML, mastermind-like; MAPK, mitogen activated protein kinase; MEK, mitogen activated protein kinase; MET, mesenchymal to epithelial transition; MST1/2, Mammalian sterile 20-like kinases; NICD, notch intracellular domain; P, phosphate group; PI3K, phosphatidylinositol 3-kinase; RAS/RAF, Rat sarcoma/rapidly accelerated fibrosarcoma; SFRP1, secreted frizzled-related protein; Smad, Caenorhabditis elegans SMA (“small” worm phenotype) and Drosophila MAD (“Mothers Against Decapentaplegic”); SOS, Son of Sevenless; TAK1, TGF β-activated kinase; TCF, T-cell factor; TEAD, transcription factor family member; TGF-β, transforming growth factor-β; WNT, wingless-type mouse mammary tumor virus integration site; YAP, yes-associated protein.