|MoBio||Axis Formation||Chapter 8|
As the embryo forms, its overall body pattern is determined by the establishment of three clear axes—the anterior-posterior axis (head-tail), the dorsal-ventral (back-belly) axis, and left-right asymmetry. The establishment of these body axes at the correct time is fundamental to normal embryonic development. For instance, the central nervous system develops along the dorsal surface, with the largest concentration of neuronal tissue—the brain—at the anterior end of the embryo. The limbs develop symmetrically and bilaterally, whereas the heart—although it begins as a symmetrical structure—ultimately comes to point toward the left side of the trunk. Some internal structures are paired (the kidneys, lungs, adrenal glands, testes, and ovaries), whereas many are not (the heart, gut, pancreas, spleen, liver, and uterus).
Information about the establishment of these body axes and their role in development is far from complete. For example, the anterior-posterior axis of the mouse blastocyst may be determined before it implants and is certainly established before gastrulation. An unanswered question, however, is whether this early embryonic axis helps determine the later development of the embryo. The early axis may play a role in primitive streak formation, and requires the expression of Wnt, which helps regulate the formation of one of embryo's chief signaling centers: the node.
An important group of cells that produces molecular signals that help determine the anterior-posterior axis of the mouse embryo is the anterior visceral endoderm (AVE). The AVE expresses different genes along its length. At embryonic day 5 (E5.0) in the mouse, for example, the Hex gene—a member of the family of homeobox genes that help regulate body patterning of the mouse embryo—is expressed in the distal visceral endoderm. These cells migrate to become the AVE, which forms on the opposite side of the embryo from the primitive streak, thus establishing the anterior-posterior axis of the fetus.
Then, between E6.0 and E7.0 in the mouse, the anterior region of the AVE, where the heart will form, expresses Mrg1. The medial region expresses the transcription factor genes Otx2 and Lim1, as well as other genes. The region of the AVE that lies next to the part of the epiblast that will give rise to oral ectoderm and the forebrain expresses Hesx1, another homeobox gene. Collectively, the AVE and the genes it expresses help regulate the development of the anterior end of the embryo.
Other genes, notably Bmp4, also help shape the mouse embryo prior to gastrulation. BMP stands for bone morphogenetic protein, a family of proteins that help regulate the differentiation of mesenchymal cells, which are derived from mesoderm, including bone-forming osteoblasts, and adipocytes, which are fat cells. They also play a role in CNS development. Bmp4, which is expressed in the extraembryonic ectoderm next to the epiblast and also in the inner cell mass of the E3.5 and E4.5 mouse blastocyst, may activate genes in epiblast cells that then migrate to form the primitive streak. Wnt3 apparently helps induce the formation of both the primitive streak and the node in mammals, although there is no evidence indicating that Wnt3 expression is required for mesoderm induction. However, formation of the embryo's head region, obviously a key anterior structure, seems to require inhibition of the activities of Wnt and Bmp4—a potential role of the AVE.
Therefore, coordinating the embryo's "decisions" about its body pattern is a hierarchy of genes. Overall, the Hox genes specify anterior-posterior polarity. Their normal function can be subverted by retinoic acid, which can activate Hox genes in inappropriate places. Less is known about the establishment of the dorsal-ventral axis. It may be determined in the blastocyst, or even in the oocyte; it is clearly established when the notochord develops. Genes such as Nodal and Lefty help determine left-right asymmetry. Genes that regulate body patterning in embryonic development are well conserved throughout evolution among both vertebrates and invertebrates.