Structure, biosynthesis and function of the developmentally regulated polysialic acid moiety of the neural cell adhesion molecule NCAM

Informations projet

N° de convention de subvention: BIO4960730

Projet clôturé

Date de début 1 Novembre 1996

Date de fin 31 Octobre 1999

Financé au titre de

• Specific research, technological development and demonstration programme in the field of biotechnology, 1994-1998

Coût total € 0,00

Contribution de l’UE Aucune donnée

Coordonné par

Medizinische Hochschule Hannover
Germany

Livrables

ST8SiaIV knock-out mice

Gene targeting in embryonic stem cells generated ST8SiaIV deficient mice. Homozygous mutants are viable and fertile. ST8SiaIV deficient mice lack PSA only in adult stages and express normal amounts of NCAM protein. These mutants allow to dissociate PSA-functions from NCAM functions in neurogenesis, axonal growth, synaptic plasticity and other functions that involve PSA-NCAM expression. Electrophysiological studies carried out with ST8SiaIV knock-out-mice demonstrated impaired long-term potentiation (LTP) and long-term depression (LTD) in CA1. The impairment is age-dependent. ST8SiaIV knock out mice may provide interesting model systems to studying growth and metastastatic potential of neuroendocrine tumors and invasion and dissemination of neuroinvasive bacteria. Mice lacking ST8SiaIV/PST-1, one of the sialyltransferases responsible for addition of polysialic acid (PSA) to NCAM. Unlike in NCAM knock-out mice, neural precursor cells in the rostral migratory stream express PSA and follow their normal pathway and mossy fibres in the hippocampal CA3 region show no signs of delamination. However, adult animals show an almost total loss of PSA, allowing to directly address its role in synaptic plasticity. Schaffer collateral-CA1 synapses showed an age dependent impairment in long-term potentiation (LTP), while LTP remained undisturbed in CA3. Given that LTP in both pathways is affected in NCAM mutants this data shows that NCAM but not PSA is likely to be essential for LTP in the CA3 region of the hippocampus

ELISA to determine PSA-NCAM in the sera of tumour patients

Neuroblastoma and other neuroendocrine tumours express PSA-NCAM. We have demonstrated that serum levels for PSA-NCAM were drastically increased in patients with advanced tumour stages and in fatal courses of the disease, while patients with differentiated tumour types and limited disease had low or normal levels. A high throughput ELISA has been developed to sensitively monitore PSA-serum levels. Neuroblastoma and other neuroendocrine tumours express PSA-NCAM. We have demonstrated that serum levels for PSA-NCAM were drastically increased in patients with advanced tumour stages and in fatal courses of the disease, while patients with differentiated tumour types and limited disease had low or normal levels. We developed a high throughput ELISA to measure PSA-serum levels with high sensitivity and reliability.