Dchs1-Fat4 regulation of osteogenic differentiation in mouse

Abstract

In human, mutations of the protocadherins FAT4 and DCHS1 result in Van Maldergem syndrome, which is characterised, in part, by craniofacial abnormalities. Here, we analyse the role of Dchs1-Fat4 signalling during osteoblast differentiation in mouse. We show that Fat4 and Dchs1 mutants mimic the craniofacial phenotype of the human syndrome and that Dchs1-Fat4 signalling is essential for osteoblast differentiation. In Dchs1/Fat4 mutants, proliferation of osteoprogenitors is increased and osteoblast differentiation is delayed. We show that loss of Dchs1-Fat4 signalling is linked to increased Yap-Tead activity and that Yap is expressed and required for proliferation in osteoprogenitors. In contrast, Taz is expressed in more-committed Runx2-expressing osteoblasts, Taz does not regulate osteoblast proliferation and Taz-Tead activity is unaffected in Dchs1/Fat4 mutants. Finally, we show that Yap and Taz differentially regulate the transcriptional activity of Runx2, and that the activity of Yap-Runx2 and Taz-Runx2 complexes is altered in Dchs1/Fat4 mutant osteoblasts. In conclusion, these data identify Dchs1-Fat4 as a signalling pathway in osteoblast differentiation, reveal its crucial role within the early Runx2 progenitors, and identify distinct requirements for Yap and Taz during osteoblast differentiation.

Making and shaping endochondral and intramembranous bones

“…The transcription factor, TWIST inhibits RUNX2 activity. C,D,G, Taken from Crespo‐Enriquez et al 296 A, angular process; co, condylar process; C, coronoid process; F, frontal bone; IM, intramembranous bone; MC, Meckel's cartilage; M, mandible; P, parietal bone…”

“…The faster proliferation rate in quails may enable cells to reach a critical density for differentiation more quickly while the higher levels of RUNX2 will promote osteocyte formation reducing the pool of proliferative osteoblasts and resulting in smaller bones—An observation made experimentally following misexpression of RUNX2 in vivo 28,275,276 . RUNX2 activity is determined by its levels of expression, posttranslational modifications by signaling pathways (eg, WNT, BMP, FGF, HIPPO, FAT4‐DCHS1) together with the presence/absence of co‐factors 296,297 . RUNX2 may also be activated by mechanical stimuli and contribute to mechanoadaptive changes in osteoblast gene expression 298,299 .…”

Localization of YAP activity in developing skeletal rudiments is responsive to mechanical stimulation

“…The effects of the Fat4 mutation have previously been analyzed in a number of organ systems including the skeleton where Mao et al demonstrated a role for Fat4 in planar cell polarity, specifically during elongation of the sternum, but independent of YAP. Recently, Crespo‐Enriquez, et al showed that Fat4 is essential for osteoblast differentiation and that mutants have abnormalities in the cranial skeleton, but the only difference seen in the appendicular skeleton at P0 was a decrease in cortical thickness at the midshaft. The specific objective of the analysis presented in this study was to ask if Fat4 −/− embryos phenocopy the effects in immobile embryos, specifically the effects at the joint where we see loss of chondrogenous layers, joint fusions and misshapen condyles and if Fat4 is expressed in the affected territories.…”

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

“…As such they possess extracellular domains which facilitate binding, as well as an intracellular domain capable of associating with adaptor and signaling proteins (9). FAT and DCHS protocadherins act as ligand-receptor pairs when expressed in adjacent cells and have been implicated both in planar cell polarity (PCP) regulating cell movements such as convergence-extension and cell migration (10,11), as well as regulation of YAP/TAZ independently of the Hippo kinase cascade (12)(13)(14), which controls tissue proliferation and stem cell activity (15).…”