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Published on: March 17, 2014
Extracellular domain of CD98hc is required for early murine development
Yukiyasu Sato1, Rachel A Heimeier, Cuiling Li
1Section on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, Program in Cellular Regulation and Metabolism (PCRM), NICHD, NIH, Bethesda, Maryland, 20892, USA. shi@helix.nih.gov.
Insights
The multifunctional protein CD98 heavy chain (CD98hc) plays stage-specific roles in mouse embryonic development. Early development relies on CD98hc
Area of Science:
- Developmental Biology
- Cell Biology
- Molecular Biology
Background:
- The multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) is crucial for embryonic development, interacting with integrin β1 for ES cell proliferation and with L-type amino acid transporters (LATs) for amino acid transport.
- CD98hc-null mice show early post-implantation lethality, similar to integrin β1-null mice, highlighting the importance of CD98hc-integrin β1 interactions.
- CD98hc's interaction with LATs is essential for amino acid and thyroid hormone transport, suggesting a role in development via these transporters.
Purpose of the Study:
- To investigate the stage-specific roles of CD98hc in murine embryonic development.
- To determine the functional consequences of a CD98hc mutation affecting its interaction with integrin β1 and LATs.
- To elucidate the distinct contributions of CD98hc's integrin signaling and amino acid transport functions to embryonic development.
Main Methods:
- Generation of mice carrying a mutant CD98hc allele (CD98hcΔ/+) encoding a ΔCD98hc-β geo fusion protein.
- Analysis of the mutant protein's interaction with integrin β1 and its localization in ES cells and reconstituted frog oocytes.
- Assessment of embryonic lethality and developmental timing in CD98hcΔ/Δ embryos.
Main Results:
- The ΔCD98hc-β geo fusion protein retained the ability to interact with integrin β1 but showed poor cell surface localization, suggesting preserved integrin signaling but impaired LAT function.
- CD98hcΔ/+ mice were phenotypically normal, but CD98hcΔ/Δ embryos exhibited lethality between embryonic day 7.5 and 9.5.
- Implantation sites in CD98hcΔ/Δ embryos sometimes lacked embryonic components by E9.5, indicating developmental failure during this period.
Conclusions:
- CD98hc plays essential roles in early post-implantation development, likely through regulating integrin-dependent signaling.
- The function of CD98hc as a component of amino acid transporters may be critical for embryonic development at later stages.
- These findings suggest distinct, stage-specific functions for CD98hc in murine embryonic development, differentiating its roles in integrin signaling versus amino acid transport.
Background:
The multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) associates with integrin β1 through its cytoplasmic and transmembrane domains and the CD98hc-mediated integrin signaling is required for maintenance of ES cell proliferation. CD98hc-null mice exhibit early post-implantation lethality similar to integrin β1-null mice, supporting the importance of its interaction with integrin β1. On the other hand, the extracellular domain of CD98hc interacts with L-type amino acid transporters (LATs) and is essential for appropriate cell surface distribution of LATs. LATs mediate the transport of amino acids and other molecules such as thyroid hormone. In this respect, CD98hc may also affect development via these transporters.
Results:
In this study, mice were generated from embryonic stem (ES) cell line (PST080) harboring a mutant CD98hc allele (CD98hcΔ/+). Expression of the CD98hc mutant allele results in ΔCD98hc-β geo fusion protein where extracellular C-terminal 102 amino acids of CD98hc are replaced with β geo. Analyses of PST080 ES cells as well as reconstituted frog oocytes demonstrated that ΔCD98hc-β geo fusion protein preserved its ability to interact with integrin β1 although this mutant protein was hardly localized on the cell surface. These findings suggest that ΔCD98hc-β geo protein can mediate integrin signaling but cannot support amino acid transport through LATs. CD98hcΔ/+ mice were normal. Although some of the implantation sites lacked embryonic component at E9.5, all the implantation sites contained embryonic component at E7.5. Thus, CD98hcΔ/Δ embryos are likely to die between E7.5 and E9.5.
Conclusions:
Considering that CD98hc complete knockout (CD98hc-/-) embryos are reported to die shortly after implantation, our findings suggest potential stage-specific roles of CD98hc in murine embryonic development. CD98hc may be essential for early post-implantation development by regulating integrin-dependent signaling, while the other function of CD98hc as a component of amino acid transporters may be required for embryonic development at later stages.
