Targeted disruption of Pax1 defines its null phenotype and proves haploinsufficiency

Abstract

The murine paired box-containing gene Pax1 is required for normal development of the vertebral column, the sternum, and the scapula. Previous studies have shown that three natural Pax1 mouse mutants, the undulated alleles, exhibit phenotypes of different severity in these skeletal elements. Nevertheless, these analyses have not clarified whether the semidominant Undulated short-tail (Un s ) mutation, in which the complete Pax1 locus is deleted, represents a null allele. Moreover, the analyses of the classical undulated mutants did not allow a conclusion with respect to haploinsufficiency of Pax1. To address both questions we have created a Pax1 null allele in mice by gene targeting. Surprisingly, the phenotype of this defined mutation exhibits clear differences to that of Un s . This result strongly indicates the contribution of additional gene(s) to the Un s mutant phenotype. Furthermore, the phenotype of mice heterozygous for the null allele demonstrates that Pax1 is haploinsufficient in some though not all skeletal elements which express Pax1 during embryonic development.

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

“…T-gene-mutant heterozygous mice exhibit short tails, and the homozygous mutant mice are embryonic lethal (Wilson and Conlon, 2002). Another example is the Pax1 knockout mice, in which an apparent kinked tail is observed only in the Pax1 null homozygotes (Wilm et al, 1998). It is possible that the observed tail abnormality was induced by the insertion of the LYL1 transgene into the genomic loci of a certain crucial gene.…”

Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation

“…Several transcription factors have been shown to play essential roles in sclerotome development like Bapx1. Pax1 is one of the transcription factors required for the axial skeleton development (Wilm et al 1998). The vertebral defects of Pax1 mutants showed remarkable similarities to those of Bapx1.…”

“…Pax1 expression is initially detected in the ventromedial part of newly segmented somites, giving rise to the sclerotome, and is con®ned to the anlagen of the intervertebral discs onwards. Pax1 mutants suffered from severely disturbed formation of both the vertebral bodies and intervertebral discs, like Bapx1 mutants (Wallin et al 1994;Wilm et al 1998). Pax9, another member of the Pax gene family, is highly homologous to Pax1, and is expressed in developing sclerotome in a overlapping pattern to that of Pax1 (Neubu Èser et al 1995).…”

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

“…These results from classical mutants suggested that Pax1 may be haploinsufficient, and would lead to perinatal lethality in the homozygous state. Indeed, targeted mutation of Pax1 proves haploinsufficiency for some, but not all sclerotomal derivatives that express Pax1 (Wilm et al, 1998). This could be due to the ectopic activation of Nkx2.2 in the absence of Pax1 (Kokubu et al, 2003), or alternatively, another gene may functionally compensate for the loss of Pax1 in unaffected sclerotome.…”