On the role of lateral stabilization during early patterning in the pancreas - PubMed (original) (raw)

On the role of lateral stabilization during early patterning in the pancreas

Walter de Back et al. J R Soc Interface. 2013 Feb.

Abstract

The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell-cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell-cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development.

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Figures

Figure 1.

Figure 1.

Interactions between transcription factors and signalling pathways. (a) Known regulatory interactions involved in the exocrine–endocrine cell fate decision in the pancreas, including contact-mediated signalling (see main text for details and references). Receptor–ligand binding in the Notch signalling pathway induces lateral inhibition. Formation of gap junctions represents one possible pathway for lateral stabilization (dashed arrow). (b) Interactions in the two-variable model in which cells i and j are coupled by lateral inhibition and lateral stabilization (see main text for details). Parameters a, b and c represent the interaction strengths. (Online version in colour.)

Figure 2.

Figure 2.

Classification of different spatial pattern domains under varying strengths of lateral inhibition a and lateral stabilization b. Colour (dark/white) indicates (high/low) expression of Y. The Roman numerals (I–V) denote different patterning domains. Solid lines indicate phase transitions with critical values ac, formula image and formula image that are found by means of bifurcation analysis. Parameters as in table 1; a and b as indicated on axes. (Online version in colour.)

Figure 3.

Figure 3.

Analysis of cell–cell interaction mechanisms in a system of two cells i and j. Phase plane analysis (a,b) and time plots of gene expression dynamics (c,d). (a) Nullclines of X (where d_X_/d_t_ = 0) under lateral inhibition. One symmetric unstable steady state (open box) and two asymmetric stable steady states (filled boxes) coexist. (b) Nullclines of Xi (solid line) and Yi (dashed line) under lateral stabilization where Yj = 1. One unstable steady state (open box) and three stable steady states (filled boxes) exist. Arrowhead indicates a ‘new’ steady state dependent on lateral stabilization. (c) Symmetry breaking in X expression. After induction, a transient of intermediate expression at the symmetric unstable steady state (arrowhead) is followed by symmetry breaking (arrow, at t = τ X) into one X+ and one _X_− cell. (d) Biphasic growth of Y in the deterministic system (η = 0 to exclude symmetry breaking of X). After induction, expression of Y remains at a plateau level (arrowhead) followed by super-induction (arrow, at t = τ Y) through lateral stabilization. Parameter values as in table 1. (Online version in colour.)

Figure 4.

Figure 4.

Scattering and cell-type ratio control by lateral stabilization. (a) Bifurcation diagram showing the steady states of Y expression of a two-cell system. Two saddle–node bifurcations are found at formula image that explain the phase transitions in figure 2. The four-variable system is projected onto a one-dimensional scale using the sum of Y expression in the couplet (Yi + Yj ). Dashed lines indicate unstable states; solid lines indicate stable states. Black lines represent globally stable states; thick lines represent states in which Y is stable but X is unstable. (b) Spatial patterns of endocrine (black) and exocrine (white) cells in a lattice simulation at different strengths of lateral stabilization b and under two conditions of noise η. Under higher noise levels, scattering is observed at the phase transition (see domain V in figure 2). Arrowheads indicate small clusters of chequerboard pattern. (c) Cell-type ratio of endocrine cells ɛ as a function of lateral stabilization strength b. Grey (η = 10−4)/black (η = 10−2) indicate noise levels. (Online version in colour.)

Figure 5.

Figure 5.

Relative timing of cell fate decisions depends on lateral stabilization b and controls patterning. (a) For formula image, symmetry breaking of X precedes super-induction of Y (formula image), resulting in chequerboard patterning (b = 15). (b) In contrast, for formula image, super-induction of Y precedes symmetry breaking of X (formula image) and results in ubiquitous exocrine cell fates (b = 35). (Online version in colour.)

References

    1. Slack JM. 1995. Developmental biology of the pancreas. Development 121, 1569–1580 - PubMed
    1. Gu G, Dubauskaite J, Melton DA. 2002. Direct evidence for the pancreatic lineage: Ngn3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447–2457 - PubMed
    1. Fishman MP, Melton DA. 2002. Pancreatic lineage analysis using a retroviral vector in embryonic mice demonstrates a common progenitor for endocrine and exocrine cells. Int. J. Dev. Biol. 46, 201–207 10.1387/ijdb.011552 (doi:10.1387/ijdb.011552) - DOI - PubMed
    1. Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA. 2007. A multipotent progenitor domain guides pancreatic organogenesis. Dev. Cell 13, 103–114 10.1016/j.devcel.2007.06.001 (doi:10.1016/j.devcel.2007.06.001) - DOI - PubMed
    1. Efrat S. 2010. Stem cell therapy for diabetes. New York, NY: Humana Press.

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