Cell death in the developing vertebrate limb: A locally regulated mechanism contributing to musculoskeletal tissue morphogenesis and differentiation

Abstract

Our aim is to critically review current knowledge of the function and regulation of cell death in the developing limb. We provide a detailed, but short, overview of the areas of cell death observed in the developing limb, establishing their function in morphogenesis and structural development of limb tissues. We will examine the functions of this process in the formation and growth of the limb primordia, formation of cartilaginous skeleton, formation of synovial joints, and establishment of muscle bellies, tendons, and entheses. We will analyze the plasticity of the cell death program by focusing on the developmental potential of progenitors prior to death. Considering the prolonged plasticity of progenitors to escape from the death process, we will discuss a new biological perspective that explains cell death: this process, rather than secondary to a specific genetic program, is a consequence of the tissue building strategy employed by the embryo based on the formation of scaffolds that disintegrate once their associated neighboring structures differentiate.

Confluence of Cellular Degradation Pathways During Interdigital Tissue Remodeling in Embryonic Tetrapods

“…Studies in a variety of models of embryonic tissue degeneration indicate that rather than being inherently programmed, cell death is locally regulated by extrinsic molecular interactions. The plasticity of the interdigital tissue in stages immediately prior to the onset of death provides solid support for the importance of extrinsic signals in the establishment of the degenerative process (see review by Montero et al, 2020). In addition, as will be discussed below, accumulating evidence has revealed that, far from being a unique way of embryonic cell death, apoptosis is only one among several redundant dying mechanisms accounting for the elimination of tissues in the course of embryonic development (Childs et al, 2014).…”

Transforming growth factor beta signaling: The master sculptor of fingers

“…The best known cell death areas are the so called Anterior Necrotic Zone (ANZ), Posterior Necrotic Zone (PNZ) and the Opaque Patch (OP) 19,20 . Additionally, the apical ectodermal ridge (AER) is an ectodermal thickening in the distal edge of the limb bud that maintains a fine-tuned equilibrium between cell death and proliferation 20 .…”

“…The best known cell death areas are the so called Anterior Necrotic Zone (ANZ), Posterior Necrotic Zone (PNZ) and the Opaque Patch (OP) 19,20 . Additionally, the apical ectodermal ridge (AER) is an ectodermal thickening in the distal edge of the limb bud that maintains a fine-tuned equilibrium between cell death and proliferation 20 . There are three main signaling regions that direct morphogenesis controlling early limb bud development: the AER; the underlying mesoderm, also known as the progress zone (PZ); and the zone of polarizing activity (ZPA) in the posterior mesenchyme of the early limb.…”

“…The AER maintains undifferentiated and proliferating the subjacent Developmental Dynamics mesodermal cell population, in an area termed the progress zone (PZ). As these cells become displaced proximally and abandon the PZ, they either differentiate into skeletal precursor cells or die and are eliminated 19,20 . Throughout this transition, the skeletal primordium of the limb develops specifically into the proximal stylopod segment (corresponding to the prospective thigh/arm area), the middle zeugopod (the prospective leg/forearm) and the distal autopod (the prospective foot/hand).…”

Histone Epigenetic Signatures in Embryonic Limb Interdigital Cells Fated to Die

“…In addition to these degradative routes, oxidative stress might exert an important role in the establishment of areas of interdigital cell death [9][10][11]. Although we do not know yet how these degenerative routes are coordinated or whether they are regulated by other signals, it has been shown that interdigit degradation is preceded by intense DNA damage and by activation of a DNA repair response [12,13]. A similar process also occurs in cancer and is associated with epigenetic alterations, such as DNA methylation or post-translational histone modifications [14].…”