Abstract
The formation of the vertebrate skeleton is orchestrated in time and space by a number of gene regulatory networks that specify and position all skeletal tissues. During embryonic development, bones have two distinct origins: bone tissue differentiates directly from mesenchymal progenitors, whereas most long bones arise from cartilaginous templates through a process known as endochondral ossification. Before endochondral bone development takes place, chondrocytes form a cartilage analgen that will be sequentially segmented to form joints; thus, in the cartilage template, either the cartilage maturation programme or the joint formation programme is activated. Once the cartilage differentiation programme starts, the growth plate begins to form. In contrast, when the joint formation programme is activated, a capsule begins to form that contains special articular cartilage and synovium to generate a functional joint. In this review, we will discuss the mechanisms controlling the earliest molecular events that regulate cell fate during skeletogenesis in long bones. We will explore the initial processes that lead to the recruitment of mesenchymal stem/progenitor cells, the commitment of chondrocyte lineages, and the formation of skeletal elements during morphogenesis. Thereafter, we will review the process of joint specification and joint morphogenesis. We will discuss the links between transcription factor activity, cell–cell interactions, cell–extracellular matrix interactions, growth factor signalling, and other molecular interactions that control mesenchymal stem/progenitor cell fate during embryonic skeletogenesis.
Highlights
The formation of the vertebrate skeletal system is a paradigmatic model process for the study of differentiation, patterning, and morphogenesis during embryogenesis
Once chondrogenesis starts in the early stages of embryogenesis, cartilage forms and is gradually replaced by bone; it persists on articular surfaces and forms the sole skeletal support system for the larynx, trachea, bronchi, and other structures
During digit formation in chicken embryos, chondrogenic differentiation begins when the TGFβ/activin signalling pathway directs the pool of mesenchymal precursor cells in the digital crescent (DC)/ phalanx-forming region (PFR) region to a cartilage fate by inducing Sox9 and Bmpr1b expression (Montero et al, 2008)
Summary
The formation of the vertebrate skeletal system is a paradigmatic model process for the study of differentiation, patterning, and morphogenesis during embryogenesis. Skeletal Stem Cells and Fate Decisions bone and cartilage development are temporally and spatially regulated to control the patterning of the early skeleton and ensure the correct shapes of all skeletal elements. LPM cells proliferate and migrate from the flanks of the embryo and form the limb buds (Vogel et al, 1996; Ohuchi et al, 1997; Jin et al, 2018) As development progresses, these initially undifferentiated cells interpret signals according to their positions and differentiate into a variety of tissues that compose the adult limb while simultaneously shaping each limb into its final form. We will focus on the cellular and molecular mechanisms that govern the early fate decisions of mesenchymal stem/progenitor cells that give rise to the appendicular skeleton, using limb development as a model. We will explore the early steps of joint specification
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