Wtap is required for differentiation of endoderm and mesoderm in the mouse embryo

Abstract

Wilms' tumor 1-associating protein (WTAP) was previously identified as a protein associated with Wilms' tumor-1 (WT-1) protein that is essential for the development of the genitourinary system. Although WTAP has been suggested to function in alternative splicing, stabilization of mRNA, and cell growth, its in vivo function is still unclear. We generated Wtap mutant mice using a novel gene-trap approach and showed that Wtap mutant embryos exhibited defective egg-cylinder formation at the gastrulation stage and died by embryonic day 10.5. Although they could form extraembryonic tissues and anterior visceral endoderm, Wtap mutant embryos and embryonic stem cells failed to differentiate into endoderm and mesoderm. The chimera analysis showed that Wtap in extraembryonic tissues was required for the formation of mesoderm and endoderm in embryonic tissues. Taken together, our findings indicate that Wtap is indispensable for differentiation of mesoderm and endoderm in the mouse embryo. Developmental Dynamics 237:618 -629, 2008.

Nuclear Degradation of Wilms Tumor 1-associating Protein and Survivin Splice Variant Switching Underlie IGF-1-mediated Survival

“…The phenotype of WTAP-null mouse embryos, for example, has indicated a role for WTAP in endoderm and mesoderm differentiation (6). Although the mechanism for this effect of WTAP is unknown, the current findings might be relevant to this question.…”

“…The precise molecular actions of WTAP are not well understood, but the importance of this protein is highlighted by the early lethality of WTAP-null mouse embryos (5,6). WTAP is widely expressed in adult tissues and might therefore play a constitutive role.…”

Identification of Wilms' Tumor 1-associating Protein Complex and Its Role in Alternative Splicing and the Cell Cycle

“…Thus, WTAP is considered to have an evolutionarily conserved role in the regulation of splicing in mammalian cells. However, the detailed molecular mechanism is not well understood, although its essential role has been established in mouse early embryo development and cell cycle regulation (17,18).…”

Modify or die? - RNA modification defects in metazoans

“…119 Interestingly, stem cells loose their ability to maintain a pluripotent state, when METTL3 or METTL14 are downregulated. 120 Consistently, knockout mice die during early embryonic development, 121,122 and cells of the inner cell mass fail to differentiate into mesoderm or endoderm. 122 Malformations of the zebrafish brain are also observed in morpholino-mediated knockdowns of the 3 conserved small nucleolar RNAs (snoRNA) U26, U44 and U78, suggesting that translation defects consistently affect brain development.…”

“…120 Consistently, knockout mice die during early embryonic development, 121,122 and cells of the inner cell mass fail to differentiate into mesoderm or endoderm. 122 Malformations of the zebrafish brain are also observed in morpholino-mediated knockdowns of the 3 conserved small nucleolar RNAs (snoRNA) U26, U44 and U78, suggesting that translation defects consistently affect brain development. 123 Finally, 2 more genes are known to cause ID: mutations in ADAT3, which is required for the formation of inosine (I 34 ) at the anticodon of several tRNAs, cause severe ID and strabismus, 124 and TRMT1, the homolog of Trm1p, is required for the formation of N2,N2-dimethylguanosine (m 2 2 G).…”