Effects of Tulp4 deficiency on murine embryonic development and adult phenotype

Genetically engineered mouse models have the potential to unravel fundamental biological processes and provide mechanistic insights into the pathogenesis of human diseases. We have previously observed that germline genetic variation at the TULP4 locus influences clinical characteristics in patients with myeloproliferative neoplasms. To elucidate the role of TULP4 in pathological and physiological processes in vivo, we generated a Tulp4 knockout mouse model. Systemic Tulp4 deficiency exerted a strong impact on embryonic development in both Tulp4 homozygous null (Tulp4-/-) and heterozygous (Tulp4+/-) knockout mice, the former exhibiting perinatal lethality. High-resolution episcopic microscopy (HREM) of day 14.5 embryos allowed for the identification of multiple developmental defects in Tulp4-/- mice, including severe heart defects. Moreover, in Tulp4+/- embryos HREM revealed abnormalities of several organ systems, which per se do not affect prenatal or postnatal survival. In adult Tulp4+/- mice, extensive examinations of hematopoietic and cardiovascular features, involving histopathological surveys of multiple tissues as well as blood counts and immunophenotyping, did not provide evidence for anomalies as observed in corresponding embryos. Finally, evaluating a potential obesity-related phenotype as reported for other TULP family members revealed a trend for increased body weight of Tulp4+/- mice.Research Highlights center dot To study the role of the TULP4 gene in vivo, we generated a Tulp4 knockout mouse model.center dot Correlative analyses involving HREM revealed a strong impact of Tulp4 deficiency on murine embryonic development.

Automated summary

Genetically engineered mouse models have the potential to uncover basic biological processes and provide mechanistic insights into human disease pathogenesis. This study reveals the impact of TULP4 deficiency on embryonic development and the clinical characteristics of myeloproliferative neoplasms. It also suggests the potential role of TULP4 in organ system abnormalities and obesity-related phenotypes.