Embracing change: striated-for-smooth muscle replacement in esophagus development

Abstract

The esophagus functions to transport food from the oropharyngeal region to the stomach via waves of peristalsis and transient relaxation of the lower esophageal sphincter. The gastrointestinal tract, including the esophagus, is ensheathed by the muscularis externa (ME). However, while the ME of the gastrointestinal tract distal to the esophagus is exclusively smooth muscle, the esophageal ME of many vertebrate species comprises a variable amount of striated muscle. The esophageal ME is initially composed only of smooth muscle, but its developmental maturation involves proximal-to-distal replacement of smooth muscle with striated muscle. This fascinating phenomenon raises two important questions: what is the developmental origin of the striated muscle precursor cells, and what are the cellular and morphogenetic mechanisms underlying the process? Studies addressing these questions have provided controversial answers. In this review, we discuss the development of ideas in this area and recent work that has shed light on these issues. A working model has emerged that should permit deeper understanding of the role of ME development and maturation in esophageal disorders and in the functional and evolutionary underpinnings of the variable degree of esophageal striated myogenesis in vertebrate species.

Fig. 1

Models of development of the esophageal ME. a Lineage progression in development of ESM. Mesp1⁺ cranial mesoderm progenitors express Tbx1 to give rise to migratory Isl⁺ ESM progenitors. It is hypothesized that after arrival at the proximal end of the esophageal ME, these cells express Pax7 and subsequently Myf5 and MyoD. The dashed arrows indicate uncertainty as to the precise linear order of this process; see text for additional details. b Model of striated myogenesis in the TZ. The TZ contains proliferating skeletal muscle-like progenitor (Pax7⁺) cells, muscle progenitor cells in the process of commitment to the skeletal muscle-like lineage (Pax7⁺/Myf5⁺/MyoD⁺ cells), myoblasts (Myf5⁺/MyoD⁺ cells), and differentiating myoblasts (myogenin⁺ [MyoG⁺] cells). The TZ moves in a proximal-distal manner, leaving ESM in its wake. SMCs are mainly found distal to the TZ where they undergo fascicular reorientation (see c). Some SMCs are also found dispersed within the TZ. c Model for reorientation of SMC fascicles and proximal-distal movement of the TZ between P0 and P14. SMCs of the circumferential layer of the ME are initially grouped into fascicles that have an end-to-end configuration and an orientation parallel to the lumen (note that, for simplicity, the external, longitudinal layers of both smooth and striated muscles are not shown in the figure). Fascicles reorganize in a distal-to-proximal manner via a globular intermediate (indicated by the tear drop-shaped cluster of SMCs) and culminate in a side-by-side configuration with an orientation that is nearly parallel to the lumen; as a consequence, the fascicles ultimately occupy only the most distal portion of the ME. The blue triangle represents a hypothetical distal signal that promotes SMC fascicular reorientation. The identity of this signal is not known. The orange triangle represents a hypothetical TZ-based signal that promotes movement of proximal SMC fascicles in the distal direction. The identity of this signal is not known but cell proliferation of ESM progenitors in the TZ may contribute to this activity. b and c are adapted from reference [26]