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Study of the sulphate exchanger Tat1 (SLC26A8) in spermatogenesis : analysis of its physiological role in mouse male germ cells and genetic investigation in the aetiology of human infertility

Objetivo

Tat1 (SLC26A8) encodes for an anionic exchanger exclusively expressed at the plasma membrane of human adult germ cells undergoing spermatogenesis. Although so far the physiological role of this molecule is unknown, it has been shown to transport sulphate i n a chloride dependant manner and it is likely to fulfil critical functions during spermatogenesis. Indeed, Tat1 belongs to a family of transporters, which physiological importance has been clearly demonstrated by association with several human disorders ( Pendred syndrome, Dyastrophic dysplasia, Congenital chloride diarrhoea). Furthermore, Tat1 regulate the transport of sulphate that we know is essential for many biological processes (i.e growth, development). For instance, hyposulphation of the proteoglycans located in the extra-cellular matrix of the cartilage, leads to dramatic bone development defects in patients diagnosed for Dyastrophic dysplasia. In order to define the physiological function of Tat1 we propose to use an RNAi based methodology to specifically down-regulate Tat1 expression in the adult mouse testis. We will take advantage of a new expression vector designed to produce siRNA-like transcripts that can specifically initiate degradation of the endogenous mRNA to which they are homologous. We propose to generate transgenic mice with constructs producing Tat1 siRNA molecules, and therefore down-regulate Tat1 expression in the appropriated tissues (so far Tat1 has been shown to be solely expressed in the adult testis). In parallel, we will elect roporate the expression vector into adult mouse testis in order to locally inhibit Tat1 expression. Combination of these two approaches should allow characterisation of the potential spermatogenesis defects associated with the lack of Tat1 activity. Subsequent search for similar abnormalities in human infertile patients will permit to investigate Tat1 implication in the aetiology of this disorder.

Ámbito científico (EuroSciVoc)

Tema(s)

Convocatoria de propuestas

FP6-2002-MOBILITY-11
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Régimen de financiación

ERG - Marie Curie actions-European Re-integration Grants

Coordinador

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
Aportación de la UE
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Coste total
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