Dynamic MAPK/ERK activity sustains nephron progenitors through niche regulation and primes precursors for differentiation
Ihermann-Hella, Anneliis; Hirashima, Tsuyoshi; Kupari, Jussi; Kurtzeborn, Kristen; Li, Hao; Kwon, Hyuk Nam; Cebrian, Cristina; Sooﬁ, Abdul; Dapkunas, Arvydas; Miinalainen, Ilkka; Dressler, Gregory R.; Matsuda, Michiyuki; Kuure, Satu (2018-09-13)
Anneliis Ihermann-Hella, Tsuyoshi Hirashima, Jussi Kupari, Kristen Kurtzeborn, Hao Li, Hyuk Nam Kwon, Cristina Cebrian, Abdul Soofi, Arvydas Dapkunas, Ilkka Miinalainen, Gregory R. Dressler, Michiyuki Matsuda, Satu Kuure, Dynamic MAPK/ERK Activity Sustains Nephron Progenitors through Niche Regulation and Primes Precursors for Differentiation, Stem Cell Reports, Volume 11, Issue 4, 2018, Pages 912-928, ISSN 2213-6711, https://doi.org/10.1016/j.stemcr.2018.08.012.
© 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
The in vivo niche and basic cellular properties of nephron progenitors are poorly described. Here we studied the cellular organization and function of the MAPK/ERK pathway in nephron progenitors. Live-imaging of ERK activity by a Förster resonance energy transfer biosensor revealed a dynamic activation pattern in progenitors, whereas differentiating precursors exhibited sustained activity. Genetic experiments demonstrate that MAPK/ERK activity controls the thickness, coherence, and integrity of the nephron progenitor niche. Molecularly, MAPK/ERK activity regulates niche organization and communication with extracellular matrix through PAX2 and ITGA8, and is needed for CITED1 expression denoting undifferentiated status. MAPK/ERK activation in nephron precursors propels differentiation by priming cells for distal and proximal fates induced by the Wnt and Notch pathways. Thus, our results demonstrate a mechanism through which MAPK/ERK activity controls both progenitor maintenance and differentiation by regulating a distinct set of targets, which maintain the biomechanical milieu of tissue-residing progenitors and prime precursors for nephrogenesis.
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