Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Lens epithelium-derived growth factor (Ledgf), also known as PC4- and SF2-interacting protein 1 (Psip1), is a chromatin-associated protein involved in gene regulation and cell survival in vitro.
• Its specific biological functions in vivo remain largely unknown.

Purpose of the Study:

• To investigate the in vivo biological function of Psip1 using a gene trap screen in mice.
• To characterize the phenotypic consequences of Psip1 disruption in a whole organism.

Main Methods:

• Identification of an embryonic stem cell clone with disrupted Psip1 via a gene trap screen.
• Generation and analysis of Psip1-deficient mice (Psip1(-/-)) to assess in vivo function and phenotypes.
• Characterization of the resulting Psip1-betageo fusion protein for retained domains and chromatin-binding activity.

Main Results:

• Psip1 disruption resulted in perinatal lethality in the majority of homozygous mice.
• Surviving adult mice exhibited a spectrum of abnormalities, including reduced fertility, absent epididymal fat pads, blepharitis, and motor/behavioral deficits.
• Mutant mice displayed craniofacial and skeletal abnormalities, such as brachycephaly, small rib cages, and homeotic skeletal transformations, suggesting a role in Hox gene regulation.

Conclusions:

• Psip1 is essential for normal embryonic development and survival in mice.
• Psip1 plays a significant role in regulating skeletal development, craniofacial morphogenesis, and motor function.
• The observed phenotypes, particularly skeletal transformations, suggest Psip1's involvement in controlling Hox gene expression, potentially linking it to myeloid leukemias involving NUP98-PSIP1 fusions.