Identification of anosmin 1 domains involved in PKR2 activity modulation

Identifier:  TFG:3003

Handle: https://hdl.handle.net/20.500.11797/TFG3003

Authors:  Muñoz López, Marina

Abstract:
Kallmann syndrome (KS) is a rare disease caused by the deficient migration of GnRH neuronal precursors, from the olfactory placode to the hypothalamus, affecting the functioning of the hypothalamic-pituitary-gonadal axis and the formation of the olfactory bulbs (OB). Patients with KS are characterized by hypogonadotropic hypogonadism and anosmia. Mutations described in ANOS1 (or KAL1), FGFR1, PKR2 and PK2 genes have been associated with this pathology. The X-linked variant of KS is caused by mutations in the ANOS1 gene, which encodes the extracellular matrix glycoprotein anosmin 1 (A1). A1 plays a key role in the migration and adhesion of various cell types in the SNC. The best known mechanism of action of A1 is its participation in the modulation of FGFR1 activation. The hypothesis of the interaction and modulation by A1 of PKR2 activity was raised. Pkr2 mutant and A1 overexpressing mice, show opposite effects on the migration of SVZ neuronal precursors and their differentiation into tyrosine hydroxylase interneurons in the OB, involving these proteins in the same biological processes. Recent studies indicate the interaction between A1 and PKR2, and the involvement of A1 Nterminal domains in PKR2 modulation. This work reveals how the C172R mutation affects the A1 WAP domain in the modulation of the subsequent activation of MAPKs ERK1/2 intracelular signaling pathways via PKR2/PK2. The results suggest that the WAP domain is essential and the C172R mutation interferes in the modulation of PKR2 activation. However, there are contradictory data on the role of CR and FnIII.1 domains of A1, whose participation must be explained by studying a mutation in the FnIII.1 domain (A1N267K) and the truncated version of A1 with the WAP-FnIII.1 domains (A1WAPFnIII.1) created in this study.