Abstract
Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplastic disorder. Affected patients present a wide spectrum of symptoms including short stature, postaxial polydactyly, and dental abnormalities. We previously disrupted Evc2, one of the causative genes for EvC syndrome, in mice using a neural crest-specific, Cre-mediated approach (i.e., P0-Cre, referred to as Evc2 P0 mutants). Despite the fact that P0-Cre predominantly targets the mid-facial region, we reported that many mid-facial defects identified in Evc2 global mutants are not present in Evc2 P0 mutants at postnatal day 8 (P8). In the current study, we used multiple Cre lines (P0-Cre and Wnt1-Cre, respectively), to specifically delete Evc2 in neural crest-derived tissues and compared the resulting mid-facial defects at multiple time points (P8 and P28, respectively). While both Cre lines indistinguishably targeted the mid-facial region, they differentially targeted the anterior portion of the skull base. By comprehensively analyzing the shapes of conditional mutant skulls, we detected differentially affected mid-facial defects in Evc2 P0 mutants and Evc2 Wnt1 mutants. Micro-CT analysis of the skull base further revealed that the Evc2 mutation leads to a differentially affected skull base, caused by premature closure of the intersphenoid synchondrosis (presphenoidal synchondrosis), which limited the elongation of the anterior skull base during the postnatal development of the skull. Given the importance of the skull base in mid-facial bone development, our results suggest that loss of function of Evc2 within the skull base secondarily leads to many aspects of the mid-facial defects developed by the EvC syndrome.
Highlights
Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondroectodermal dysplasia (McKusick et al, 1964)
In a comparison between global and P0-Cre-mediated Evc2 mutants, we reported that at postnatal day 8 (P8): (1) Evc2 P0 mutants somewhat recapitulate craniofacial and tooth phenotypes exhibited by Evc2 global mutant mice and that (2) many mid-facial defects identified in the Evc2 global mutants are not present in the Evc2 P0 mutants (Kwon et al, 2018)
Evc2 deletion mediated by the P0-Cre (Evc2fl/fl; P0-Cre, abbreviated as Evc2 P0 mutants) leads to an overall shortened head and delayed mandibular incisor eruption at postnatal day 8 (P8) (Figure 1A)
Summary
Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondroectodermal dysplasia (McKusick et al, 1964). Genetic studies have allowed identification of two causative genes for EvC syndrome, EVC and EVC2, Evc Function in Mid-Facial Development and homozygous mutations in either have been linked to two-thirds of EvC patients (Ruiz-Perez et al, 2003). Our previous studies interestingly identified the bovine ortholog EVC2/LIMBIN as a causative gene for chondrodysplasia in Japanese brown cattle (Takeda et al, 2002). Recent studies identify EVC2/LIMBIN mutations in dwarf Tyrolean Gray cattle (Murgiano et al, 2014). These two studies suggest an evolutionarily conserved function of EVC2 among different species
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.