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WIREs Dev Biol
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Regulation of size and scale in vertebrate spinal cord development

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Abstract All vertebrates have a spinal cord with dimensions and shape specific to their species. Yet how species‐specific organ size and shape are achieved is a fundamental unresolved question in biology. The formation and sculpting of organs begins during embryonic development. As it develops, the spinal cord extends in anterior–posterior direction in synchrony with the overall growth of the body. The dorsoventral (DV) and apicobasal lengths of the spinal cord neuroepithelium also change, while at the same time a characteristic pattern of neural progenitor subtypes along the DV axis is established and elaborated. At the basis of these changes in tissue size and shape are biophysical determinants, such as the change in cell number, cell size and shape, and anisotropic tissue growth. These processes are controlled by global tissue‐scale regulators, such as morphogen signaling gradients as well as mechanical forces. Current challenges in the field are to uncover how these tissue‐scale regulatory mechanisms are translated to the cellular and molecular level, and how regulation of distinct cellular processes gives rise to an overall defined size. Addressing these questions will help not only to achieve a better understanding of how size is controlled, but also of how tissue size is coordinated with the specification of pattern. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Signaling Pathways > Global Signaling Mechanisms Nervous System Development > Vertebrates: General Principles
Overview of neural tube development and organization. (a) Top view of a mouse embryo at embryonic day E8.5. Neuromesodermal progenitors (NMPs) in caudal lateral epiblast (CLE) give rise to both neural progenitors and presomitic mesoderm (PSM). Anterior (A) top, posterior (P) bottom. Primitive streak (PS), lateral plate mesoderm (LPM). (b) Transverse sections through the mouse neural tube and underlying notochord at different stages of development. The neural progenitors form a single cell layered pseudostratified epithelium, with their apical side (A) facing the lumen of the neural tube. The dorsal (D) to ventral (V), and apical (A) to basal (B) lengths of the neuroepithelium increase over time. The dorsoventral pattern of progenitor domains pd1 to p3, floor plate (FP), and roof plate (RP) is specified in response to the morphogen gradients of Shh, Wnts and BMPs. Progenitors differentiate into postmitotic neurons (*) that delaminate basally from the epithelium and form a lateral mantle zone (gray)
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Scaling of pattern with tissue size. (a) A simplified morphogen‐controlled gene regulatory network in the spinal cord. Shh and BMP signals activate expression of dorsal (D), intermediate (I) and ventral (V) target genes, which repress each other. Input from uniformly expressed activators is marked with gray arrows. This system results in the formation of three adjacent domains of D, I, V expression as shown in (b). (b) A possible model of growth and pattern for two individuals that have tissues with different initial sizes. In both individuals throughout the initial specification phase of development (t1), the opposing gradients have decay lengths that scale with tissue size and identical amplitudes. The morphogen‐driven network in (a) leads to the formation of dorsal (D), intermediate (I) and ventral (V) domains along the DV axis. The levels of morphogen signaling at the boundaries between domains in both cases are the same. During the neurogenesis phase (t2), the tissues have expanded in DV length by uniform proliferation, the levels of signaling of both morphogens have decreased. The pattern is maintained by the downstream gene regulatory network (a). Progenitors in the V domain begin differentiating into postmitotic neurons at a rate independent of tissue size, allowing for progenitor domain proportions to be maintained between individuals
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Gene regulatory networks controlling progenitor specification, neuronal differentiation and cell cycle progression in the spinal cord. (a) The identities of p3, pMN, and p2 progenitors in the ventral neural tube are regulated by the expression of transcription factors, such as Nkx2.2, Olig2, Pax6, and Irx3. Starting from ~E9 of mouse development, the pMN progenitors differentiate at a higher rate than progenitors from p2 and p3 domains (Kicheva et al., 2014). (b) A simplified diagram of the interactions between the gene regulatory networks involved in cell fate specification, neuronal differentiation and cell cycle regulation. Shared genes from these GRNs are key in coordinating the specification of progenitor identities, the transition from progenitors to postmitotic neurons, and the cell cycle dynamics (Lacomme, Liaubet, Pituello, & Bel‐Vialar, 2012; Lobjois et al., 2008; Sagner et al., 2018). Components of these GRNs are controlled by the extrinsic factors, such as morphogens. Many components and interactions are omitted
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Determinants of tissue size. (a) The final tissue size is determined by the initial size, given similar growth rate. (b) Cell proliferation allows for exponential increase in cell number. (c) Cells can be eliminated through apoptosis leading to a reduction in tissue size. Apoptotic cells become fragmented and are extruded from the epithelium. (d) Progenitors differentiate into postmitotic neurons at a specific rate. Postmitotic neurons delaminate out of the neuroepithelium leading to a reduction in the size of the progenitor domain. (e, f) With time, cells undergo changes in their size (e) and shape (f) altering the absolute dimensions of the epithelium. (g) Tissues can grow at different rates in different directions, leading to changes in tissue shape
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Nervous System Development > Vertebrates: General Principles
Signaling Pathways > Global Signaling Mechanisms
Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing