Transcription factor Foxc1 is involved in anterior part of cranial base formation

Abstract

The cranial base is a structure mainly formed through endochondral ossification and integrated into the craniofacial complex, which acts as an underlying platform for the developing brain. Foxc1 is an indispensable regulator during intramembranous and endochondral ossification. In this study, we found that the spontaneous loss of Foxc1 function in a mouse (congenital hydrocephalous), Foxc1 , demonstrated the anterior cranial base defects, including unossified presphenoid and lack of middle part of the basisphenoid bone. Hypoplastic presphenoid primordial cartilage (basal portion of the trabecular cartilage [bTB]) and a lack of the middle part of basisphenoid primordial cartilage (the hypophyseal cartilage) were consistently observed at earlier developmental stage. Foxc1 was expressed robustly and ubiquitously in undifferentiated mesenchyme of the cranial base-forming area in E11.0 wild-type fetuses. Once chondrogenesis commenced, the expression was downregulated and later limited to the perichondrium. Detection of transcripts of Collagen type2 A1 (Col2a1) revealed that both bTB and the anterior part of the hypophyseal cartilage developing anterior to the persistent epithelial stalk of the anterior lobe of the pituitary gland were suppressed in the Foxc1 . Proliferation activity of chondrocyte precursor cells was higher in the Foxc1 . Loss of Foxc1 function only in the neural crest cell lineage (Wnt1-cre;Foxc1 ) showed ossification of the posterior part of the hypophyseal cartilage derived from the mesoderm. These findings suggest that Foxc1 is an important regulator to further chondrogenesis and initiate the ossification of the presphenoid and basisphenoid bones.

The Transcription Factor Foxc1 Promotes Osteogenesis by Directly Regulating Runx2 in Response of Intermittent Parathyroid Hormone (1–34) Treatment

“…In our research, we revealed that the upregulation of Foxc1 expression appeared at an early stage in osteogenic differentiation in vitro. Researchers also found that Foxc1 was detected in ectoderm and craniofacial mesenchyme of mouse embryos at E8.5 and in the first zygomatic arch at E9.5, while Runx2 was detected in the osteogenic precursor matrix at E10.5, suggesting the potential regulating effect of Foxc1 on Runx2 in osteogenic differentiation (Sun et al, 2013a;Mya et al, 2018b). Such hypothesis was confirmed by luciferase reporter assay, and it turned out that Foxc1 could enhance the transcriptional activity of Runx2.…”

“…Meanwhile, the regulation of osteogenesis usually involves the collaborative activities of several signaling proteins and transcription factors (Hopkins et al, 2016b). Foxc1, which belongs to the transcription factors family named as Forkhead box or FOX genes, has an essential impact on regulation of intramembranous and endochondral ossification in normal development and bone formation (Mya et al, 2018a). Foxc1 null embryos displayed bony fusion of maxilla and mandible, accompanied by defects in maxilla, mandible, and agenesis of the temporomandibular joint (Inman et al, 2013).…”

Cell lineage‐ and expression‐based inference of the roles of forkhead box transcription factor Foxc2 in craniofacial development

“…Indeed, knockout of either gene in mice mildly affects the formation of the middle ear, 3,4,30 and Foxc2 −/− mice exhibit a small otic capsule, but this does not seem to be a severe deformation 4 . As for the cranial base, Foxc2 −/− mice show non‐ossification of the presphenoid, 3,4 while Foxc1 ch/ch mice exhibit non‐ossification of the presphenoid, severe loss in the anterior part of the basisphenoid, and a deformed alisphenoid 31 . Based on these phenotypes, together with the similar expression profile of these genes, it is suggested that Foxc1 plays a more vital role in basisphenoid and alisphenoid development than Foxc2 , while the two genes are equally responsible for the development of other cranial base components in which they are co‐expressed.…”

“…Indeed, Foxc1 and Foxc2 demonstrate cooperative activity during embryogenesis of the eye, 19 kidney, 20 heart, 21 and vasculature 15,22‐25 . The roles of Foxc1 in craniofacial development has been relatively well‐investigated 12‐14,26‐31 . In contrast, although Foxc2 participates in craniofacial morphogenesis, 3,4 the detailed functioning of Foxc2 in this region has yet to be explored.…”

Gene‐specific facial dysmorphism in Axenfeld‐Rieger syndrome caused by FOXC1 and PITX2 variants

“…PITX2 protein plays a critical role in early development of structures in the front part of the eye, as well as the pituitary cells, teeth, heart, and abdominal organs (Franco et al, 2014). FOXC1 protein is a transcriptional partner of GLI2 highly expressed in undifferentiated mesenchyme and is thought to play a regulator role in chondrogenesis, initiating the ossification of cranial base bones important for craniofacial morphogenesis (Mya et al, 2018; Yoshida et al, 2015).…”