Morphogen gradients provide positional information during development. To uncover the minimal requirements for morphogen gradient formation, we have engineered a synthetic morphogen in Drosophila wing primordia. We show that an inert protein, green fluorescent protein (GFP), can form a detectable diffusion-based gradient in the presence of surface-associated anti-GFP nanobodies, which modulate the gradient by trapping the ligand and limiting leakage from the tissue. We next fused anti-GFP nanobodies to the receptors of Dpp, a natural morphogen, to render them responsive to extracellular GFP. In the presence of these engineered receptors, GFP could replace Dpp to organize patterning and growth in vivo. Concomitant expression of glycosylphosphatidylinositol (GPI)–anchored nonsignaling receptors further improved patterning, to near–wild-type quality. Theoretical arguments suggest that GPI anchorage could be important for these receptors to expand the gradient length scale while at the same time reducing leakage.
Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals’ brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a Glycogen Synthase Kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9,000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single nucleotide variants (SNVs) in these individuals compared to psychiatrically-unaffected controls. Many of these SNVs alter Wnt/β-catenin signaling activity of the neurally-predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/β-catenin pathway.
The application of synthetic biology approaches to study development opens the possibility to build and manipulate developmental processes to understand them better. Researchers have reconstituted fundamental developmental processes, such as cell patterning and sorting, by engineering gene circuits in vitro. Moreover, new tools have been created that allow for the control of developmental processes in more complex organoids and embryos. Synthetic approaches allow testing of which components are sufficient to reproduce a developmental process and under which conditions as well as what effect perturbations have on other processes. We envision that the future of synthetic developmental biology requires an increase in the diversity of available tools and further efforts to combine multiple developmental processes into one system.
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