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Cell populations at the start of organogenesis
Specification of the Body Axes and The Body Plan
Embryos can be thought of as being constructed with three orthogonal spatial axes (cephalocaudal, dorsoventral and laterolateral), plus a temporal axis. In mammalian embryos, axes cannot be specified at very early stages: embryonic axes can be defined only after the early extraembryonic structures have been formed and the inner cell mass can be seen. The position of the future epiblast can be predicted in human embryos when the hollow blastocyst has formed. The inner cell mass becomes (seemingly) randomly located on the inside of the trophectoderm and forms a population of epiblast cells subjacent to the trophoblast. This region implants first. It is not known whether the trophectoderm in contact with the inner cell mass initiates implantation, so that the future dorsal surface of the embryo is closest to the disrupted maternal vessels at the implantation site, or whether the inner cell mass can travel around the inside of the trophoblast to gain a position subjacent to the implantation site once implantation has started.
Axes may be conferred on the whole embryonic disc, which is initially flat and mainly two-dimensional. However, their subsequent orientation in the folded three-dimensional embryo will be completely different. The dorsal structures of the folded embryo form from a circumscribed central ellipse of the early flat embryonic disc (see Fig. 10.5 ). Lateral and ventral structures form from the remainder of the disc, and the peripheral edge of the disc eventually becomes constricted at the umbilicus (see Figs 10.9 – 10.10 ). Although the appearance of part of the epiblast is taken to specify the dorsal surface of the embryo, the inner layer, i.e. the hypoblast, is not, by default, a ventral embryonic structure.
The primary, cephalocaudal, axis is conferred by the appearance of the primitive streak in the bilaminar disc. The primitive streak patterns cells during ingression, and so also specifies the dorsoventral axis, which becomes apparent after embryonic folding. The position of ingression through the streak confers axial, medial or lateral characteristics on the forming mesenchyme cells. The axial and medial populations remain as dorsal structures in the folded embryo, and the surface ectoderm above them will exhibit dorsal characteristics. The lateral plate mesenchyme will assume lateral and ventral positions after embryonic folding, and the surface ectoderm above this population will gain ventral characteristics. The third and last spatial axis is the bilateral, or laterolateral, axis, which appears as a consequence of the development of the other two axes. Initially, the right and left halves of the embryonic body are bilaterally symmetric. Lateral projections, the upper and lower limbs, develop in two places on each side of the body wall (somatopleure).
With the last axis established, the temporal modification of the original embryonic axes can be seen. The segmental arrangement of the cephalocaudal axis is very obvious in the early embryo and is retained in many structures in adult life. Similarly, dorsal embryonic structures remain dorsal and undergo relatively little change. However, structures that were originally midline and ventral, especially those derived from splanchnopleuric mesenchyme, e.g. the cardiovascular system and the gastrointestinal tract and its adnexae, are subject to extensive shifts, and change from a bilaterally symmetric arrangement to an entire body that is now chiral, i.e. has distinct left and right sides.
Organogenesis, the development of all the body organs and systems, begins after the dramatic events of gastrulation, when the embryo has attained a recognizable body plan. In human embryos, this corresponds to the end of stage 10 ( Fig. 12.1 ). The head and tail folds are well formed, with enclosure of the foregut and hindgut (proenteron and metenteron), although the midgut (mesenteron) is only partly constricted from the yolk sac. The forebrain projection dominates the cranial end of the embryo, and the buccopharyngeal membrane and cardiac prominence are caudal and ventral to it. The cardiac prominence contains the transmedian pericardial cavity, which communicates dorsocaudally with right and left pericardioperitoneal canals. These pass dorsally to the transverse septum mesenchyme and open caudally into the extraembryonic coelom on each side of the midgut. The intraembryonic mesenchyme has begun to differentiate and the paraxial mesenchyme is being segmented into somites. Neural groove closure is progressing caudally, so that a neural tube is forming between the newly segmenting somites. Rostrally, the early brain regions, which have not yet fused, can be discerned. The neuroepithelium is separated from the dorsal aspect of the gut by the notochord. The earliest blood vessels have appeared and a primitive tubular heart occupies the pericardium. The chorionic circulation is soon to be established, after which the embryo rapidly becomes completely dependent on the maternal blood stream for its requirements. The embryo is connected to the developing placenta by a mesenchymal connecting stalk in which the umbilical vessels develop, and that also contains the allantois, a hindgut diverticulum. The lateral body walls are still widely separated. The embryo has contact with three different vesicles, namely, the amnion, which is in contact with the surface ectoderm; the yolk sac, which is in contact with the endoderm; and the chorionic cavity, containing the extraembryonic coelom, which is in contact with the intraembryonic coelomic lining (see Fig. 10.10 ).
The early body plan of the embryo is segmented. The boundaries between the segments are maintained by the differential expression of genes and proteins that restrict cell migration in these regions. Organogenetic processes either retain the segmental plan, e.g. spinal nerves, or replace it locally, e.g. the modifications of somatic intersegmental vessels by the development of longitudinal anastomoses. Anomalies may result from improper specification of segments along the cephalocaudal axis and may fail to produce the appropriately modified segmental plan.
The degree to which vertebrate embryos are developmentally constrained at this period of development is controversial. Comparative studies on the timing at which specific embryonic structures appear, heterochrony, have shown that other embryonic species do not follow the same developmental sequence as humans ( ). Although some developmental mechanisms are highly conserved, e.g. the homeobox gene codes, others may have been dissociated and modified in different vertebrate species during evolution.
Organogenesis, the further development of body regions and organs that is described in this Section, starts from about stage 10 (postfertilization days 28–29). Although it is both conventional and convenient to consider the further development of each body system on an individual basis, not only do all systems develop simultaneously, but also they interact and modify each other as they develop. This necessary interdependence is supported by the evidence of experimental embryology and reinforced by the phenomena of growth anomalies, which cut across the artificial boundaries of systems in most instances. For these reasons, it is recommended that the development of an individual system or body region should be studied in relation to others, especially those most closely associated with it, whether spatiotemporally or causally.
Embryonic Cell Populations at the Start of Organogenesis
The developmental processes operating in the embryo between stages 5 and 9 enabled the construction of the bi- and trilaminar embryonic disc, the intraembryonic coelom and new proliferative epithelia. From the end of stage 10 a range of local epithelial and mesenchymal populations now interact to produce viscera and appendages. The inductive influences on these tissues and their repertoire of responses are very different from those seen at the onset of gastrulation. The range of tissues present at the start of organogenesis, when the body plan is clear, is given below (see Fig. 12.1 ; Fig. 12.2 ). A summary of the fates of the embryonic cell populations is given in Fig. 12.3 .
Epithelial populations in the embryo
All epithelial populations express the cell polarity genes Crumbs , Scribbl e and Baz/PAR-3 ( Ch. 10 ). They all display apical specializations, including primary cilia and microvilli, juxtaluminal junctions and, when not actively dividing, temporally and spatially specified basal laminae. Movement of fluid or proteins is limited between epithelial populations, creating barriers between developing tissues and organs.
Surface ectoderm
During embryogenesis, the surface ectoderm shows regional differences in thickness. Ectoderm over the dorsal region of the head and trunk is thin, as is the pericardial covering; this has been interpreted as a consequence of the expansion of this epithelium over structures that are enlarging rapidly as development proceeds. After the surface ectoderm has completed a number of early interactions it forms an upper layer, the periderm, which remains throughout fetal life, and a lower layer which differentiates into epidermis.
Ectodermal ring and ectodermal placodes
The ectoderm on the head and lateral borders of the embryo shows a zone of epithelial thickening, the ectodermal ring, which can be discerned from stage 10 and is completed by stage 12. Rostrally, it contains populations of neuroectoderm that remain in the ectoderm after primary neurulation and are termed ectodermal placodes. The latter may be considered to be neuroepithelial cells that remain within the surface ectoderm until central nervous system development has progressed sufficiently for their inclusion into sensory epithelia and cranial nerve ganglia. The neuronal placodes may either invaginate in toto to form a vesicle, or remain as a neuronal layer, or contribute individually to neuronal structures with cells of other origins. A midline ectodermal thickening, the adenohypophysial placode, invaginates as Rathke's pouch and forms a vesicle immediately rostral to the buccopharyngeal membrane. The ectodermal ring then passes bilaterally to encompass the olfactory and optic placodes, which give rise to the olfactory sensory epithelium and the lens of the eye, respectively. It then overlays the pharyngeal arches, where it gives rise to epibranchial placodes which remove themselves individually from the ectoderm at stage 10–11 and become associated with the neural crest cells within the cranial sensory ganglia supplying the arches. It also forms specializations of the ectoderm on the frontonasal, maxillary and mandibular processes, which give rise to the tooth buds and the outer coating of the teeth. The paired otic placodes overlying the rhombencephalon at the lateral portion of the second pharyngeal arch invaginate to form the otic vesicles, which give rise to the membranous labyrinth of the ear. The ectodermal ring then passes over the occipital and cervicothoracic parts of the embryo, superficial to the four occipital somites and later to the occipitocervical junction. Further caudally, it is associated with the upper limb field, where it will give rise to the apical ectodermal ridge. have called the portion of the ring between the upper and lower limbs the intermembral part. It overlies the underlying intraembryonic coelom, and later (between stages 12 and 13), the mesonephric duct and ridge. In stages 14–15 this portion of the ectodermal ring gives rise to the mammary line. In the unfolded embryo, caudal to the lower limb field, the ring passes distal to the cloacal membrane. In the folded embryo, this region becomes superior to the cloacal membrane and corresponds to the ectoderm associated with the external genitalia, particularly the genital tubercle and urogenital swellings, where it influences the internal and external descent of the testis and the formation of the inguinal canal.
Neural ectoderm
The neuroepithelium at the time of primary neurulation is pseudostratified. It has a midline hinge region, which, with concomitant wedging of the cells in the lateral wall of the neural groove, promotes neural tube formation. The processes of the neuroepithelium abut on to internal and external limiting membranes. This epithelium proliferates to form all the cell lines of the central nervous system and, via the production of neural crest, all the cell lines of the peripheral nervous system.
Notochord
During stage 10 the notochordal plate undergoes a process that is similar to, but a mirror image of, neurulation, and forms an epithelial tube from caudal to rostral, ending with the pharynx. The notochordal plate forms a deep groove, the vertical edges of the groove move medially and touch, and then the endodermal epithelium from each side fuses ventral to the notochord. The cells swell and develop an internal pressure (turgor) that confers rigidity on the notochord. The notochord is surrounded by a basal lamina, which is initially connected to a basement membrane, referred to as a perinotochordal sheath ( ); this term is subsequently applied to mesenchymal populations that surround the notochord. After stage 11 the tubular notochord is in contact with the neural tube dorsally and the endoderm ventrally. It is not a proliferative epithelium, but it has inductive effects on the overlying neural tube and the adjacent somites, and later provides a focus for sclerotomal migration.
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