The control of tissue growth

During animal development cell proliferation must be tightly coordinated with differentiation. For each body part to develop properly, there must be sufficient proliferation to provide enough cells to form the final structure. There must also be mechanisms to ensure that proliferation is terminated and that differentiation of specific cell types begins at the correct times. Finally, there must be mechanisms to ensure that each body part will be proportioned correctly, both in relation to itself and to the rest of the organism. Although critical to animal development, how these processes are controlled and coordinated with each other remain largely unknown and are therefore a current focus in biology. We have been investigating this problem in two contexts during Drosophila development: the compound eye and the control of dorsal appendage size.

Cell proliferation during eye development. The adult fly eye is comprised of approximately 800 units, called ommatidia, which are packed in a regular hexagonal array (Ready et al. 1976). Each ommatidium contains a collection of eight photoreceptor cells and eleven accessory cells. These cell types form in a stereotyped and lineage-independent manner in the wake of a morphogenetic furrow (MF) that sweeps across the eye imaginal disc during the third larval instar stage of Drosophila development. The MF initiates at the posterior (P) margin of the eye disc and moves across the disc in the anterior (A) direction. Ahead (anterior) of the MF cells are not committed to any particular cell type and divide in an unsynchronized manner (Wolff and Ready 1991). These uncommitted cells express Hth and Exd. As the MF moves across the disc, it coordinates the cell cycle and initiates photoreceptor differentiation, in part by inducing the expression of the proneural gene, atonal (ato) and repressing Hth and Exd (Jarman et al. 1994; Baker et al. 1996; Dominguez 1999; reviewed by Baker 2001; see figure below). Behind (posterior) the MF, ommatidia form in a step-wise manner as additional cells are recruited to join the R8 cell.

We are interested in deciphering the other factors and signals that are involved in the transition from a proliferative state to a differentiated state, using the fly eye as the model system.

Below is a summary of the expression patterns in the eye disc during development; see Bessa et al. for details.

Bessa J, Gebelein B, Pichaud F, Casares F, Mann RS. Combinatorial control of Drosophila eye development by eyeless, homothorax, and teashirt. Genes Dev. 2002 Sep 15;16(18):2415-27.

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Selector gene control of organ size. The size of the dorsal appendage in Drosophila provides another system to analyze how proliferation during development is controlled. In the second thoracic segment (T2), this appendage is the wing, while in the third thoracic segment (T3), this appendage is modifed to become a balancing organ called the haltere. We know, largely from the work of E.B. Lewis, G. Morata, and their colleagues, that the haltere differs from the wing because the former expresses the Hox gene Ubx while the latter does not. Among the differences between these two appendages is size: at the end of larval development the haltere primordia has amassed ~5-fold fewer cells than the wing primordia. We found Ubx modifies the growth of the haltere by modifying both the amount and diffusion of the morphogen Decapentaplegic (Dpp). To modify Dpp diffusion, Ubx transcriptionally regulates at least two cell surface molecules, the type I Dpp receptor Thickveins (Tkv) and the glypican Dally. See Crickmore and Mann (2006, 2007) for the complete story.

We are pusuing these studies to identify additional Ubx-regulated genes involved in proliferation control, and determining which targets are directly regulated by Ubx.

Relevant papers:

Crickmore, M. and Mann, RS. (2006) Hox control of organ size by regulation of morphogen production and mobility. Science (Article). 2006 Jul 7;313(5783):63-8.

Crickmore, M. and Mann, RS.(2007) Hox control of morphogen mobility and organ development through regulation of glypican expression. Development, 2007 Jan;134(2):327-34

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