What is bad in cancer is good in the embryo: importance of EMT in neural crest development

Abstract

Although the epithelial to mesenchymal transition (EMT) is famous for its role in cancer metastasis, it also is a normal developmental event in which epithelial cells are converted into migratory mesenchymal cells. A prime example of EMT during development occurs when neural crest (NC) cells emigrate from the neural tube thus providing an excellent model to study the principles of EMT in a nonmalignant environment. NC cells start life as neuroepithelial cells intermixed with precursors of the central nervous system. After EMT, they delaminate and begin migrating, often to distant sites in the embryo. While proliferating and maintaining multipotency and cell survival the transitioning neural crest cells lose apicobasal polarity and the basement membrane is broken down. This review discusses how these events are coordinated and regulated, by series of events involving signaling factors, gene regulatory interactions, as well as epigenetic and post-transcriptional modifications. Even though the series of events involved in NC EMT are well known, the sequence in which these steps take place remains a subject of debate, raising the intriguing possibility that, rather than being a single event, neural crest EMT may involve multiple parallel mechanisms.

Figure 1

Schematic of neural crest development in the chicken embryo showing that (1A) a rostrocaudal gradient of BMP4 is inhibited by caudally expressed Noggin. The BMP4 gradient in the neural tube, which mediates the timing of neural crest EMT, itself starts rostrally and proceeds caudally as the neural tube closes. FGF8 signaling from the paraxial mesoderm maintains Noggin and is inhibited by retinoic acid signaling (RA) also in a rostrocaudal gradient. Once EMT is complete, mesenchymal neural crest cells emigrate from the neural tube and migrate to their target sites. The black lines mark the axial levels at three transverse levels, representing the gradual progress of EMT (B–D). (1B) FGF secreted from the paraxial mesoderm is required for the specification of the neural crest cells and induces expression of Noggin and Msx1/2 in the dorsal neural folds. These in turn, in the presence of Wnt expressed by the non-neural ectoderm, drives expression of Pax3/7 and Zic1. Apicolaterally bound adherens junction protein N-cadherin maintains the adhesion and polarity of the whole neural epithelium. (1C) RA secreted by the somites induces Wnt1, which induces BMPsignalling and inhibits Noggin. BMP4 is the inducer of the de-epithelization and depolarization factors in a subset of the dorsal neural tube cells that become neural crest. The apicolateral localization of N-cadherin is degraded and replaced by Cadherin 6B in the dorsal neural tube. (1D) The mesenchymal neural crest cells emigrate where the basal lamina is locally ruptured. Cadherin 6B is downregulated by Snail2 and the migratory neural crest cells start to express Cadherin 7/11. som= somite, nt= neural tube, np= neural plate, a= anterior, p= posterior, nne= non-neural ectoderm, pm= paraxial mesoderm, bm= basement membrane, ap= apical side, not= notochord, nf= neural folds, mncc= migratory neural crest cell.

Figure 1

Schematic of neural crest development in the chicken embryo showing that (1A) a rostrocaudal gradient of BMP4 is inhibited by caudally expressed Noggin. The BMP4 gradient in the neural tube, which mediates the timing of neural crest EMT, itself starts rostrally and proceeds caudally as the neural tube closes. FGF8 signaling from the paraxial mesoderm maintains Noggin and is inhibited by retinoic acid signaling (RA) also in a rostrocaudal gradient. Once EMT is complete, mesenchymal neural crest cells emigrate from the neural tube and migrate to their target sites. The black lines mark the axial levels at three transverse levels, representing the gradual progress of EMT (B–D). (1B) FGF secreted from the paraxial mesoderm is required for the specification of the neural crest cells and induces expression of Noggin and Msx1/2 in the dorsal neural folds. These in turn, in the presence of Wnt expressed by the non-neural ectoderm, drives expression of Pax3/7 and Zic1. Apicolaterally bound adherens junction protein N-cadherin maintains the adhesion and polarity of the whole neural epithelium. (1C) RA secreted by the somites induces Wnt1, which induces BMPsignalling and inhibits Noggin. BMP4 is the inducer of the de-epithelization and depolarization factors in a subset of the dorsal neural tube cells that become neural crest. The apicolateral localization of N-cadherin is degraded and replaced by Cadherin 6B in the dorsal neural tube. (1D) The mesenchymal neural crest cells emigrate where the basal lamina is locally ruptured. Cadherin 6B is downregulated by Snail2 and the migratory neural crest cells start to express Cadherin 7/11. som= somite, nt= neural tube, np= neural plate, a= anterior, p= posterior, nne= non-neural ectoderm, pm= paraxial mesoderm, bm= basement membrane, ap= apical side, not= notochord, nf= neural folds, mncc= migratory neural crest cell.

Figure 1

Schematic of neural crest development in the chicken embryo showing that (1A) a rostrocaudal gradient of BMP4 is inhibited by caudally expressed Noggin. The BMP4 gradient in the neural tube, which mediates the timing of neural crest EMT, itself starts rostrally and proceeds caudally as the neural tube closes. FGF8 signaling from the paraxial mesoderm maintains Noggin and is inhibited by retinoic acid signaling (RA) also in a rostrocaudal gradient. Once EMT is complete, mesenchymal neural crest cells emigrate from the neural tube and migrate to their target sites. The black lines mark the axial levels at three transverse levels, representing the gradual progress of EMT (B–D). (1B) FGF secreted from the paraxial mesoderm is required for the specification of the neural crest cells and induces expression of Noggin and Msx1/2 in the dorsal neural folds. These in turn, in the presence of Wnt expressed by the non-neural ectoderm, drives expression of Pax3/7 and Zic1. Apicolaterally bound adherens junction protein N-cadherin maintains the adhesion and polarity of the whole neural epithelium. (1C) RA secreted by the somites induces Wnt1, which induces BMPsignalling and inhibits Noggin. BMP4 is the inducer of the de-epithelization and depolarization factors in a subset of the dorsal neural tube cells that become neural crest. The apicolateral localization of N-cadherin is degraded and replaced by Cadherin 6B in the dorsal neural tube. (1D) The mesenchymal neural crest cells emigrate where the basal lamina is locally ruptured. Cadherin 6B is downregulated by Snail2 and the migratory neural crest cells start to express Cadherin 7/11. som= somite, nt= neural tube, np= neural plate, a= anterior, p= posterior, nne= non-neural ectoderm, pm= paraxial mesoderm, bm= basement membrane, ap= apical side, not= notochord, nf= neural folds, mncc= migratory neural crest cell.

Figure 1

Schematic of neural crest development in the chicken embryo showing that (1A) a rostrocaudal gradient of BMP4 is inhibited by caudally expressed Noggin. The BMP4 gradient in the neural tube, which mediates the timing of neural crest EMT, itself starts rostrally and proceeds caudally as the neural tube closes. FGF8 signaling from the paraxial mesoderm maintains Noggin and is inhibited by retinoic acid signaling (RA) also in a rostrocaudal gradient. Once EMT is complete, mesenchymal neural crest cells emigrate from the neural tube and migrate to their target sites. The black lines mark the axial levels at three transverse levels, representing the gradual progress of EMT (B–D). (1B) FGF secreted from the paraxial mesoderm is required for the specification of the neural crest cells and induces expression of Noggin and Msx1/2 in the dorsal neural folds. These in turn, in the presence of Wnt expressed by the non-neural ectoderm, drives expression of Pax3/7 and Zic1. Apicolaterally bound adherens junction protein N-cadherin maintains the adhesion and polarity of the whole neural epithelium. (1C) RA secreted by the somites induces Wnt1, which induces BMPsignalling and inhibits Noggin. BMP4 is the inducer of the de-epithelization and depolarization factors in a subset of the dorsal neural tube cells that become neural crest. The apicolateral localization of N-cadherin is degraded and replaced by Cadherin 6B in the dorsal neural tube. (1D) The mesenchymal neural crest cells emigrate where the basal lamina is locally ruptured. Cadherin 6B is downregulated by Snail2 and the migratory neural crest cells start to express Cadherin 7/11. som= somite, nt= neural tube, np= neural plate, a= anterior, p= posterior, nne= non-neural ectoderm, pm= paraxial mesoderm, bm= basement membrane, ap= apical side, not= notochord, nf= neural folds, mncc= migratory neural crest cell.

Figure 2

The separate subdivisions of EMT that all need to be completed for the proper amount of multipotent neural crest cells to emigrate from the neural tube. This figure outlines the results of multiple studies obtained in several species. i=inhibitory role.