An agent-based model of the Notch signaling pathway elucidates three levels of complexity in the determination of developmental patterning.

BACKGROUND: The Notch signaling pathway is involved in cell fate decision and developmental patterning in diverse organisms. A receptor molecule, Notch (N), and a ligand molecule (in this case Delta or Dl) are the central molecules in this pathway. In early Drosophila embryos, these molecules determine neural vs. skin fates in a reproducible rosette pattern. RESULTS: We have created an agent-based model (ABM) that simulates the molecular components for this signaling pathway as agents acting within a spatial representation of a cell. The model captures the changing levels of these components, their transition from one state to another, and their movement from the nucleus to the cell membrane and back to the nucleus again. The model introduces stochastic variation into the system using a random generator within the Netlogo programming environment. The model uses these representations to understand the biological systems at three levels: individual cell fate, the interactions between cells, and the formation of pattern across the system. Using a set of assessment tools, we show that the current model accurately reproduces the rosette pattern of neurons and skin cells in the system over a wide set of parameters. Oscillations in the level of the N agent eventually stabilize cell fate into this pattern. We found that the dynamic timing and the availability of the N and Dl agents in neighboring cells are central to the formation of a correct and stable pattern. A feedback loop to the production of both components is necessary for a correct and stable pattern. CONCLUSIONS: The signaling pathways within and between cells in our model interact in real time to create a spatially correct field of neurons and skin cells. This model predicts that cells with high N and low Dl drive the formation of the pattern. This model also be used to elucidate general rules of biological self-patterning and decision-making.

Translating dyslexia across species.

Direct relationships between induced mutation in the DCDC2 candidate dyslexia susceptibility gene in mice and changes in behavioral measures of visual spatial learning have been reported. We were interested in determining whether performance on a visual-spatial learning and memory task could be translated across species (study 1) and whether children with reading impairment showed a similar impairment to animal models of the disorder (study 2). Study 1 included 37 participants who completed six trials of four different virtual Hebb-Williams maze configurations. A 2 × 4 × 6 mixed factorial repeated measures ANOVA indicated consistency in performance between humans and mice on these tasks, enabling us to translate across species. Study 2 included a total of 91 participants (age range = 8-13 years). Eighteen participants were identified with reading disorder by performance on the Woodcock-Johnson III Tests of Achievement. Participants completed six trials of five separate virtual Hebb-Williams maze configurations. A 2 × 5 × 6 mixed factorial ANCOVA (gender as covariate) indicated that individuals with reading impairment demonstrated impaired visuo-spatial performance on this task. Overall, results from this study suggest that we are able to translate behavioral deficits observed in genetic animal models of dyslexia to humans with reading impairment. Future studies will utilize the virtual environment to further explore the underlying basis for this impairment.