Dosage Effects of Cohesin Regulatory Factor PDS5 on Mammalian Development: Implications for Cohesinopathies

Abstract

Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B−/− mice. While Pds5A−/− and Pds5B−/− mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A−/− or Pds5B−/− mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS.

The cohesin-interacting protein, precocious dissociation of sisters 5A/sister chromatid cohesion protein 112, is up-regulated in human astrocytic tumors

“…1). In adult mice, high expression of Pds5A mRNA has been reported in the thymus, testis, spleen and lung (36), whereas the brain and kidney displayed intermediate expression and the heart, liver, prostate and stomach, low expression (36). Also, in human organs, Pds5A expression was very broad and is consistent with our data (25).…”

“…It is a putative tumor suppressor (63,64). It has also been reported that Pds5B can functionally compensate for Pds5A loss (36,65). Therefore, the lack of the above-mentioned effects in our knockdown experiments could be due to the activity of Pds5B in these cells.…”

“…7) (42,65,66), although the exact mechanism remains unclear. Pds5A could also function during embryonic development (36,67) and tumorigenesis (25,26). In addition, signalling pathways could have some influence on the regulation of Pds5 protein family members.…”

“…It has been shown that Pds5 could be involved in the establishment, maintenance and dissolution of cohesion in both yeasts and humans (27)(28)(29)(30)34,35). It could also be implicated in embryonic development (36). The structure of S. cerevisiae Pds5p contains ~26 HEAT repeats suggesting that it could act as a scaffold protein with numerous sites for binding the globular domains of other proteins (27).…”

Loss of a cohesin-linked suppressor APRIN (Pds5b) disrupts stem cell programs in embryonal carcinoma: an emerging cohesin role in tumor suppression

“…APRIN/Pds5B mutations in the germ line, on the other hand, were shown to contribute to Cornelia de Lange-type birth defects in mice and in humans (Zhang et al, 2009). APRIN, therefore, has a unique double role: its defects in the germ line induce systemic malformations, whereas its disruptions in somatic cells result in cancer.…”