Coordinated morphogenesis of coupled tissues: supracellular cables in neurulation

Congenital malformations are common causes of perinatal mortality or lifelong disability. Most do not have generalisable genetic bases, and their prevention has scarcely improved during the molecular/genomic revolution of biology. They are caused by failures of multi-tissue, physical processes which shape organ rudiments: morphogenesis. Understanding tissue shape emergence requires unification of molecular and mechanical mechanisms. By combining quantitative imaging(1,2) with computational simulations(3-5), we helped explain how deficiencies in individual cell behaviours, studied in isolation, stall closure of the neural tube (NT) and cause spina bifida. We also demonstrated that redressing force imbalances improves NT closure(6,7). What remains unknown is how tissues initiate, adapt and terminate cellular force-generation in coordination with physically coupled structures. Leveraging new technologies, in silico models and interdisciplinary collaborations, my group is poised to address the hypothesis that force-generating cell behaviours are: i. initiated in the required place and time by ‘morphogen’ positional information, ii. fine-tuned in magnitude through mechano-molecular feedback, and iii. actively terminated when their morphogenetic objective is achieved. As an experimental system, we will study supracellular actomyosin cables, described as ‘master coordinators’(8) of morphogenesis. This research will identify mechanisms which enable embryos to robustly develop functional shapes, and their failures which cause congenital malformations.