J Korean Neurosurg Soc.  2021 May;64(3):359-366. 10.3340/jkns.2020.0359.

Embryonal Neuromesodermal Progenitors for Caudal Central Nervous System and Tissue Development

• Shaker MR
• Lee JH
• Sun W

• KMID: 2515491
• DOI: http://doi.org/10.3340/jkns.2020.0359

Abstract

Neuromesodermal progenitors (NMPs) constitute a bipotent cell population that generates a wide variety of trunk cell and tissue types during embryonic development. Derivatives of NMPs include both mesodermal lineage cells such as muscles and vertebral bones, and neural lineage cells such as neural crests and central nervous system neurons. Such diverse lineage potential combined with a limited capacity for self-renewal, which persists during axial elongation, demonstrates that NMPs are a major source of trunk tissues. This review describes the identification and characterization of NMPs across multiple species. We also discuss key cellular and molecular steps for generating neural and mesodermal cells for building up the elongating trunk tissue.

Keyword

Neuromesodermal progenitors; Axial elongation; Spinal cord development; Neurulation; Neural tube

Figure

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  Fig. 1. The process and lineage of neurulation in vertebrate embryos. A and B : Comparison of primary and secondary neurulation. A : Transition in the morphology of neuroepithelium derived from the neuroectodermal cells during primary neurulation to establish the primary neural tube. The neuroepithelium initially undergoes neural folding that bends to adhere and fuse at both ends forming the primary neural tube. Mouse primary neurulation occurs between E8–E10 [47]. Chick primary neurulation occurs between HH4–HH14, whereas human primary neurulation takes place between Carnegie stages 8–12 [37]. B : Organization of cells at the onset (up) and completion (below) of secondary neurulation in vertebrates. The tail bud cells which are NMPs, differentiate into pre-neural cells that aggregate and integrate with the primary neural tube during axial elongation. Mouse secondary neurulation starts at E12 and ends at E14 [47], whereas in chick and humans, it ends at HH35 [26] and Carnegie stage 18 [37], respectively. Although the term secondary neural tube refers to the product of secondary neurulation, secondary neurulation occurs during axial elongation and it contributes to the elongation of the neural tube. Therefore, secondary neurulation is conceptually equal to the axial elongation. C : The central nervous system development model of neuroectodermal and neuromesodermal lineage contribution toward body neural axis formation and extension in mouse. The neuroectodermal cells contribute to the brain and brachial development. The mouse NMPs generate the tail in addition to the spinal cord. NEct : neuroectodermal cells, NMPs : neuromesodermal progenitors, HH : Hamburger and Hamilton.

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  Fig. 2. Differentiation of neuromesodermal progenitors and their molecular niche during the formation of posterior tissues. Overview of the molecular niche demonstrating the relationship between signaling and genes during the differentiation of NMPs toward neural and mesodermal lineages. Both Wnt and FGF signals in the primitive streak promote the induction of NMPs. RA emanating from the newly formed somites inhibits Wnt/FGF signaling that maintains NMP self-renewal and fosters neural cell differentiation from NMPs. Newly formed neural cells in the neural tube respond to shh emanating from the notochord and Wnt/BMP emanating from the roof plate to differentiate toward motor neurons and sensory neurons/neural crest cells, respectively. Wnt activates BraT expression, which in turn promotes Wnt expression, establishing a positive feedback loop in NMPs. BraT itself can inhibit RA signaling. NMPs exposed to high Wnt differentiate toward paraxial mesodermal cells which maintain BraT expression but start to express Tbx6 and Msgn1. Tbx6 itself can activate Wnt signaling, creating a positive feedback loop in paraxial mesodermal cells. These cells later have the capacity to induce somites which become the vertebrates, or to generate muscle and mesenchymal stem cells. Sall4 acts upstream to induce mesodermal cells from NMPs via activation of Wnt and inhibition of RA signaling. Sall4 itself directly interacts with Wnt/FGF to maintain the NMP population. FGF : fibroblast growth factor, BraT : Brachyury T, RA : retinoic acid, NMPs : neuromesodermal progenitors.

Reference

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