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

目标是完成NDST同工酶1-4在小鼠中的差异作用的研究，特别强调大脑发育和免疫功能，这两者在我之前的工作中都被发现依赖于NDST功能。在过去的三年中，我产生了nst -3缺陷突变小鼠（条件和系统性），目前正在分析中。nst -1缺失的小鼠表现出一种非常类似于无前脑畸形的情况，无前脑畸形是人类大脑和颅骨发育中最常见的缺陷，与SHH （Sonic Hedgehog）信号有关。本研究的重点是NDST和HS在哺乳动物前脑（前脑）发育过程中SHH信号传导的关键作用。此外，在一些后代（无前脑畸形）中可以检测到前脑的普遍生长减少，这表明nst -1在生长因子（最有可能是FGF-8）信号传导中起着额外的作用。目前也在t细胞中特异性灭活NDST-1（通过在lack启动子控制下，将条件NDST敲除小鼠与表达cree -recombinase的小鼠杂交），研究其对免疫功能的影响，有待完成。

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.