In infants and pre-pubertal adolescents, teratomas and yolk-sac tumors are detected in gonads, cranium or along the body midline. These tumors characteristically consist of tissues of all three germ layers and are generally benign in nature, with rare malignant transformation. It is assumed that the precursor cells of these tumors are primordial germ cells/ gonocytes which fail to progress into spermatogonia ;3;4] and transform into embryonal carcinoma cells which appear at embryonic day 15.5. Knowledge of the regulatory network of germ cell specification, maintenance and differentiation is required to further understand the molecular basis of this malignancy and some of the molecular key players have been determined in the past years. Specification of murine primordial germ cells occurs at E6.75 and is mediated by BMP signaling, which leads to induction of Prdm1 and Prdm14. PRDM1 together with PRDM14 are viewed as the key regulators since they orchestrate the reacquisition of pluripotency and repression of the somatic program in PGCs. They are characterized by a highly conserved DNA-binding and dimerization motif at the C-terminus. AP-2 transcription factors bind to DNA as functional dimers and their activation is mediated by an N-terminal transactivation domain. Tfap2c is expressed in murine PGCs shortly after their specification from E7.25 up to E12.5 after they have migrated and colonized the genital ridges. In this study, we demonstrated that Htt plays important roles in the differentiation of ESCs into ectoderm, endoderm and mesoderm, and in the subsequent specification and maturation of both neural and non-neural Sibutramine HCl organ-specific lineages. In addition, we showed that Htt is involved in cell survival during germ layer specification. Our study also suggests that impairments of Notch, Hes1 and STAT3 signaling pathways may be implicated in these developmental events. Moreover, we also demonstrate that the HD pathogenic mutation differentially alters the integrity of a subset of these developmental processes without adverse effects on early embryonic cell survival. A previous report by MacDonald et al. revealed that the loss of Htt resulted in embryonic defects ranging from head-fold involution and altered neuroectodermal gene expression to mesodermal impairments, including a shortened primitive streak and absence of the embryonic organizer. However, from this important study, it was unclear whether the patterning abnormalities observed were a consequence of primary defects in either cell specification or cell survival programs. To circumvent the difficulties associated with the study of pre-implantation blastocyst in vivo, we decided to use ES cell culture protocols employing Htt KO and mutant Q111 ESC with appropriate control ESC lines to dissect the roles of Htt in these early developmental events. We demonstrated that the impairments in specification of mesendodermal and neuroectodermal cell types arising from the absence of Htt cannot be attenuated even in Catharanthine sulfate response to the strong inductive influences of the gradient morphogens, Wnt3A and RA that are essential for mediating these embryonic patterning events, indicating that Htt is involved in germ layer specification. Indeed, these observations are complementary to our previous findings of a spectrum of impairments in neural induction and early neurogenesis in knock-out Htt cell line. Htt KO neural stem cells have also been shown to harbor impaired mobility and increase oxidative damage. However, we also observed persistent and enhanced cell death in KO ESCs, which suggest that alterations in the profiles of KO EB-derived germ layer elaboration may also be secondary to differential impairments in germ layer cell survival.