A vital role for glycosphingolipid synthesis during development and differentiation

Abstract

Glycosphingolipids (GSLs) are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking. We have investigated their roles in development and differentiation by eliminating the major synthesis pathway of GSLs through targeted disruption of the Ugcg gene encoding glucosylceramide synthase. In the absence of GSL synthesis, embryogenesis proceeded well into gastrulation with differentiation into primitive germ layers and patterning of the embryo but was abruptly halted by a major apoptotic process. In vivo, embryonic stem cells deficient in GSL synthesis were again able to differentiate into endodermal, mesodermal, and ectodermal derivatives but were strikingly deficient in their ability to form well differentiated tissues. In vitro, however, hematopoietic and neuronal differentiation could be induced. The results demonstrate that the synthesis of GSL structures is essential for embryonic development and for the differentiation of some tissues and support the concept that GSLs are involved in crucial cell interactions mediating these processes.

Carbohydrate-dependent signaling from the phosphatidylglucoside-based microdomain induces granulocytic differentiation of HL60 cells

“…Most recent studies show that cholesterol can also be modified with glucose (36). These glycosylated lipids play significant roles in a variety of biological processes, including cellular proliferation, development, differentiation, and stress responses (35,37). Thus, we expected that PhGlc might also have potential roles in mammalian cells.…”

Gangliosides as apoptotic signals in ER stress response

“…[48][49][50] Although no human diseases have yet been identified in which pathogenesis is attributed to genetic deficiency of any glycosyltransferase, the analyses of these genetically engineered null mice are beginning to identify the functions of complex gangliosides in development and cell differentiation. For instance, deficiency of glucosylceramide synthase gene (Ugcg), which eliminates the major pathway of ganglioside synthesis, 51 does not adversely affect growth rate, and differentiation in vitro, but impairs embryonic development and differentiation of some tissues in vivo. 51 In contrast, b-1,4-N-acetylgalactosaminyltransferase (GalNAcT)-knockout mice express predominantly GM3-and GD3-gangliosides in their CNS, but have virtually normal CNS development and a normal lifespan.…”

“…For instance, deficiency of glucosylceramide synthase gene (Ugcg), which eliminates the major pathway of ganglioside synthesis, 51 does not adversely affect growth rate, and differentiation in vitro, but impairs embryonic development and differentiation of some tissues in vivo. 51 In contrast, b-1,4-N-acetylgalactosaminyltransferase (GalNAcT)-knockout mice express predominantly GM3-and GD3-gangliosides in their CNS, but have virtually normal CNS development and a normal lifespan. 52 The outcome of these studies can be explained, at least in part, by a possible compensatory mechanism in which precursors of complex gangliosides take over some of the functions attributed to the end products.…”

GD1b-Derived Gangliosides Modulate FcεRI Endocytosis in Mast Cells

“…Because gangliosides are related to many disease processes (Hakomori 1996a;Yamashita et al 1999), they provide an attractive target for drug therapy and diagnosis. Gangliosides play an important role in tumor progression and metastasis (Birkle et al 2003;Deng et al 2000).…”