Regulation of skeletogenic differentiation in cranial dermal bone

Abstract

Although endochondral ossification of the limb and axial skeleton is relatively well-understood, the development of dermal (intramembranous) bone featured by many craniofacial skeletal elements is not nearly as well-characterized. We analyzed the expression domains of a number of markers that have previously been associated with endochondral skeleton development to define the cellular transitions involved in the dermal ossification process in both chick and mouse. This led to the recognition of a series of distinct steps in the dermal differentiation pathways, including a unique cell type characterized by the expression of both osteogenic and chondrogenic markers. Several signaling molecules previously implicated in endochondrial development were found to be expressed during specific stages of dermal bone formation. Three of these were studied functionally using retroviral misexpression. We found that activity of bone morphogenic proteins (BMPs) is required for neural crest-derived mesenchyme to commit to the osteogenic pathway and that both Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP, PTHLH) negatively regulate the transition from preosteoblastic progenitors to osteoblasts. These results provide a framework for understanding dermal bone development with an aim of bringing it closer to the molecular and cellular resolution available for the endochondral bone development.

Closely related bird species demonstrate flexibility between beak morphology and underlying developmental programs

“…Bmp4 expression around the pnc is known to cause a marked expansion of this skeletal tissue, as exemplified in L. noctis (Fig. 3) and in previous studies (9,11,21). However, Bmp4 is primarily expressed in the pmx of stage 30 L. violacea and L. portoricensis embryos, and therefore the pnc of these two species does not expand (compare their pnc with that of L. noctis in Fig.…”

“…To establish which molecules regulate the pmx in L. violacea and L. portoricensis, we examined the expression of other skeletogenic factors known to control avian craniofacial development (18)(19)(20)(21). We found that in these two species, early in development Bmp4 is primarily expressed in domains coinciding with their developing pmx (compare the bone condensation in Fig.…”

Recapitulating cranial osteogenesis with neural crest cells in 3-D microenvironments

“…Sox9 is a well-known marker for chondrogenic cells in the process of endochondral ossification, but it also plays an important role in the differentiation of CNCCs to early bone progenitor cells during intramembranous ossification [19]. Accordingly, we detected the elevated levels of Sox9 expression during the early phase of the osteogenic differentiation, which then decreased below the initial level at the later stages of the culture process ( Figure 3B).…”

“…These findings indicate there is no chondrogenic tissue formation and the osteogenic differentiation is through the intramembraneous course. Early phases of the osteogenesis process are directly regulated by Runx2, an early marker and regulator of many other osteoblast markers, such as Bsp, Ocn and Alp [19]. In our 3-D differentiation system, RUNX2 was expressed during the first week of osteogenesis and its expression decreased significantly at the later stages of bone tissue culture ( Figure 4G).…”

“…Cranial dermal bones are unique in the way they are formed -dermal bones form directly from the neural crest of the cranial dermis without forming a cartilage precursor, through a process known as intramembranous ossification [12,[14][15][16][17][18][19][20]. Despite these unique developmental features of the cranial bones, most of our current understanding of bone development, in general, is from studies on the limb and trunk bones of mesodermal origin.…”