Abstract
Nephrogenesis is driven by complex signaling pathways that control cell growth and differentiation. The endoplasmic reticulum chaperone calreticulin (Calr) is well known for its function in calcium storage and in the folding of glycoproteins. Its role in kidney development is still not understood. We provide evidence for a pivotal role of Calr in nephrogenesis in this investigation. We show that Calr deficiency results in the disrupted formation of an intact nephrogenic zone and in retardation of nephrogenesis, as evidenced by the disturbance in the formation of comma-shaped and s-shaped bodies. Using proteomics and transcriptomics approaches, we demonstrated that in addition to an alteration in Wnt-signaling key proteins, embryonic kidneys from Calr−/− showed an overall impairment in expression of ribosomal proteins which reveals disturbances in protein synthesis and nephrogenesis. CRISPR/cas9 mediated knockout confirmed that Calr deficiency is associated with a deficiency of several ribosomal proteins and key proteins in ribosome biogenesis. Our data highlights a direct link between Calr expression and the ribosome biogenesis.
Highlights
Kidney organogenesis is characterized by a succession of morphogenetic events that is driven by cell growth and differentiation
In order to investigate whether Calr knockout impacts kidney development, mouse embryos at stage E13.5 were prepared from Calr+/− pregnant mice (Figure 1A)
The staining of embryonic kidney sections confirmed the extent of the alteration in the expression of the ribosomal proteins; no Rps10 or Rps6 could be detected in Calr−/− embryonic kidney sections (Figure 7B)
Summary
Kidney organogenesis is characterized by a succession of morphogenetic events that is driven by cell growth and differentiation. The mesenchymal– epithelial transition (MET) and the ureteric bud (UB) branching, which is the result from reciprocal induction between the UB and the metanephric mesenchyme (MM) [1], are the driving forces for the nephron formation During this process a complex and reciprocal interaction of various signaling pathways is necessary to orchestrate epithelial differentiation and the formation of the nephron [1,2,3]. Among the key pathways in this process, the glia derived neurotrophic factor (Gdnf) signaling via its Ret receptor plays a central role during a process called ureteric budding Disruption of this signaling may cause ectopic ureter or renal agenesis when the signaling is completely absent [4]. Apart from the Gdnf/Ret signaling, the canonical Wnt/β-catenin signaling is known to coordinate multiple aspects of renal development within both the MM and UB [5] and the inhibition of canonical Wnt signaling in the ureteric bud lineage and nephron progenitors results in renal agenesis [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
