B01 The role of the nephronophthisis Anks6 module in development and tissue homeostasis

26

27

  • B01
    • Walz
    • Kammerer
  • B02
    • Köttgen
  • B04
    • Bergmann
  • B06
    • Lausch
    • Schmidts
  • B07
    • Lienkamp
    • Arnold

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29

  • Z01
    • Nitschke
    • Eimer
  • Z02
    • Brox
    • Ronneberger
Gerd Walz

Gerd Walz

Principal investigator of
Bernd Kammerer

Bernd Kammerer

Principal investigator of

Mutations of NPH proteins (NPHP) cause nephronophthisis (NPH), an autosomal recessive form of cystic kidney disease accompanied by multiple extrarenal manifestations. NPHPs localize to the cilium as well as other cellular compartments including the nucleus. Although some disease manifestations are explained by structural or functional defects of the cilium, several observations suggest an involvement of NPHPs in other cellular programs, including cell polarity, cell cycle control and DNA damage response. NPHPs appear to engage in complex protein networks to execute tissue-specific functions. One of the challenges in the field is to understand the dynamic regulation of these protein complexes. We recently identified a novel NPH member, Anks6 (NPHP16), which interacts with several other NPH proteins, including NPHP2, NPHP3 and NPHP9. Both Anks6 and NPHP2 are ankyrin repeat proteins that are modified by HIF1AN, an oxygen-sensing hydroxylase. Mass spectrometric (MS) analysis suggests that the Anks6 complex also interacts with mitochondrial proteins as well as with other ankyrin-repeat and NEK proteins. This project will address four fundamental issues. The first aim will examine the time- and organ-specific composition of Anks-containing protein complexes. Anks complex composition will be validated in vivo, using Xenopus and zebrafish model systems. The second aim examines the link between Anks proteins and mitochondrial functions. The rationale for this aim results from the recent implication of mitochondria in NPH as well as the association of Anks3 and Anks6 with mitochondrial proteins. The third aim will focus on the role of the Anks-NEK module in cell cycle control and DNA damage response. The fourth aim will examine the function of Anks proteins in metabolic pathways to understand how mutations of NPH gene products alter cell metabolism and signaling networks. Collectively, this proposal will elucidate the dynamic regulation of NPHP complexes, and characterize the cellular programs controlled by the Anks3/Anks6 module. Advances will not only help to understand and predict disease manifestations, but also potentially uncover novel pathways amendable for therapeutic interventions.