Research Article

Coordination of progenitor specification and growth in mouse and chick spinal cord

Science  26 Sep 2014:
Vol. 345, Issue 6204,
DOI: 10.1126/science.1254927

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Structured Abstract


The hallmarks of development are tissue growth and the generation of cell diversity, resulting in reproducibly patterned animals. Yet, how growth and cell fate specification are coordinated to determine the variety of cell types and the proportions of their populations is not well understood. The specification of cell types can be controlled by long-range signals, called morphogens. In some tissues, the shape of morphogen gradients is controlled to match the rate at which the tissue grows, which may keep the pattern proportional to the overall tissue size. To understand whether a similar strategy applies to the patterning of the spinal cord, we measured growth and cell fate specification in chick and mouse embryos of normal size, as well as mutant mice of smaller size.


Growth and patterning of the spinal cord. Progenitors are organized in a striped pattern, revealed by their gene expression. In animals of different size, the pattern changes in the same way as the spinal cord grows. This is controlled sequentially, first by progenitor specification by opposing morphogen gradients (bottom left), then by cell-type–specific differentiation resulting in differently shaped clones (green, bottom right).


Morphogen gradients emanating from the dorsal and ventral sides of the spinal cord establish a striped pattern of gene expression in neural progenitors along the dorsoventral axis. Ventrally, Sonic Hedgehog (Shh) is the key morphogen. As the tissue grows in size, the levels of Shh activity in progenitors decrease and are not constant at progenitor domain boundaries. This prompted us to examine whether growth contributed to pattern formation. To this end, we measured the four parameters that control the number of progenitors in a domain: (i) cell proliferation, (ii) cell death, (iii) terminal differentiation of progenitors into postmitotic neurons, and (iv) switches in cell identity—morphogen-driven changes in gene expression respecifying one progenitor type into another.


Unlike systems in which pattern is proportional to size, we found that the relative dorsoventral sizes of neural progenitor domains change continuously during development . These changes in proportions are conserved between mouse, chick, and smaller mouse mutants. Because the proliferation rate of progenitors was spatially uniform and cell death was negligible, neither of these processes could account for the dynamics of pattern formation. Instead, the data revealed two distinct phases of spinal cord development. Initially, the influence of the morphogens dominates, and switches in cell identity establish pattern. During the second phase, domain-specific differentiation rates emerge, causing changes in the relative proportions of progenitor cell populations. Clonal analysis indicated that this effect is anisotropic: Differentiation affects dorsoventral and apicobasal, but not anterioposterior, domain growth. The outcome is that different domains grow in register along the anterioposterior axis. Consistent with the two-phase model, the switches in cell fate and the sensitivity to changes in morphogen signaling decrease as development proceeds. Conversely, experimentally flattening the difference in differentiation rate between domains during the second phase alters pattern.


The data reveal two phases of neural tube development and show that sequential control of progenitor cell specification and differentiation elaborates pattern without requiring signaling gradients to expand as tissues grow. Control of the differentiation rate is likely to contribute to pattern formation in other tissues. Furthermore, the domain-specific regulation of the differentiation rates could suggest a means to achieve reproducible development despite differences in individual size.

Differentiation rates regulate pool sizes

Even though a basketball player is bigger than a gymnast, their neural tubes are organized in the same way. Studying chick and mouse embryos, Kicheva et al. show that rates of cell differentiation are key (see the Perspective by Pourquie). In a two-phase process, signaling sweeps through the neural tube early on to establish some aspects of cell fate, but later, pools of progenitor cells take on their own regulation. A progenitor that differentiates is no longer a progenitor, and thus the rate of differentiation determines the size of the progenitor pool. The relative sizes of progenitor pools shift as development progresses, to build the spinal cord so that everyone, large or small, has the right proportion of each component.

Science, this issue p. 10.1126/science.1254927; see also p. 1565


Development requires tissue growth as well as cell diversification. To address how these processes are coordinated, we analyzed the development of molecularly distinct domains of neural progenitors in the mouse and chick neural tube. We show that during development, these domains undergo changes in size that do not scale with changes in overall tissue size. Our data show that domain proportions are first established by opposing morphogen gradients and subsequently controlled by domain-specific regulation of differentiation rate but not differences in proliferation rate. Regulation of differentiation rate is key to maintaining domain proportions while accommodating both intra- and interspecies variations in size. Thus, the sequential control of progenitor specification and differentiation elaborates pattern without requiring that signaling gradients grow as tissues expand.

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