Differential roles of the N-acetylglucosamine N-deacetylase/N-sulfotransferase (NDST) isozymes 1-4 in the development of the mouse

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The objective is the completion of studies on the differential effects of NDST isoenzymes 1-4 in the mouse, with particular emphasis on brain development and immune function, both of which were discovered to depend on NDST function during my previous work. In the past three years, I generated mutant mice defective in NDST-3 (conditional and systemic) which are currently being analyzed. Mice in which NDST-1 was deleted show a condition strongly resembling holoprosencephaly, the most common defect of brain und cranial development in humans associated with SHH (Sonic Hedgehog) signaling. This procet focuses on the critical role of NDST and HS for SHH signaling in the developing mammalian prosencephalon (forebrain). Moreover, a general growth reduction of the prosencephalon can be detected in some offspring (Aprosencephaly), suggesting an additional role of NDST-1 in growth factor (most likely FGF-8) signaling. NDST-1 is also currently being specifically inactivated in T-cells (by crossing conditional NDST knockout mice with mice expressing cre-recombinase under the control of the lck promoter) in order to study the effect on immune function, which needs to be completed.