title: A developmental transcriptomic analysis ofPax1andPax9in embryonic intervertebral disc development.
abstract: Pax1andPax9play redundant, synergistic functions in the patterning and differentiation of the sclerotomal cells that give rise to the vertebral bodies and intervertebral discs (IVD) of the axial skeleton. They are conserved in mice and humans, whereby mutation/deficiency of humanPAX1/PAX9has been associated with kyphoscoliosis. By combining cell-type-specific transcriptome and ChIP-sequencing data, we identified the roles ofPax1/Pax9in cell proliferation, cartilage development and collagen fibrillogenesis, which are vital in early IVD morphogenesis.Pax1is up-regulated in the absence ofPax9, whilePax9is unaffected by the loss ofPax1/Pax9We identified the targets compensated by a single- or double-copy ofPax9They positively regulate many of the cartilage genes known to be regulated by Sox5/Sox6/Sox9and are connected toSox5/Sox6by a negative feedback loop.Pax1/Pax9are intertwined with BMP and TGF-B pathways and we propose they initiate expression of chondrogenic genes during early IVD differentiation and subsequently become restricted to the outer annulus by the negative feedback mechanism. Our findings highlight how early IVD development is regulated spatio-temporally and have implications for understanding kyphoscoliosis.
authors.affiliation: The Single Cell Biology Laboratory, The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: V
authors.initials: V
authors.lastname: Sivakamasundari
authors.affiliation: Department of Biology, Clarkson University, 8 Clarkson Avenue, Potsdam, NY 13699, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Kraus
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis Street, 138672, Singapore.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Sun
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis Street, 138672, Singapore.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis Street, 138672, Singapore.
authors.forename: Siew Lan
authors.initials: SL
authors.lastname: Lim
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis Street, 138672, Singapore.
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Department of Biology, Clarkson University, 8 Clarkson Avenue, Potsdam, NY 13699, USA tlufkin@clarkson.edu.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-7902-4771
authors.initials: T
authors.lastname: Lufkin
keywords: BMP; Intervertebral disc; Pax1; Pax9; Sox trio; TGF-B