Extracellular adhesion molecules and their neuronal receptors guide the growth and branching of axons and dendrites. Growth cones are attracted to intermediate targets, but they must switch their response upon arrival so that they can move away and complete the next stage of growth. Here, we show that KPC-1, a C. elegans Furin homolog, regulates the level of the branching receptor DMA-1 on dendrites by targeting it to late endosomes. In kpc-1 mutants, the level of DMA-1 is abnormally high on dendrites, resulting in trapping of dendrites at locations where a high level of the cognate ligand, the adhesion molecule SAX-7/L1, is present. The misregulation of DMA-1 also causes dendritic self-avoidance defects. Thus, precise regulation of guidance receptors creates flexibility of responses to guidance signals and is critical for neuronal morphogenesis.
- Hugo J Bellen, Howard Hughes Medical Institute, Baylor College of Medicine, United States
© 2016, Dong et al.
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Mutations in the RNA helicase, DDX3X, are a leading cause of Intellectual Disability and present as DDX3X syndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet, the cellular and molecular mechanisms by which DDX3X controls cortical development are largely unknown. Here, using a mouse model of Ddx3x loss-of-function we demonstrate that DDX3X directs translational and cell cycle control of neural progenitors, which underlies precise corticogenesis. First, we show brain development is sensitive to Ddx3x dosage; complete Ddx3x loss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition, Ddx3x loss is sexually dimorphic, as its paralog, Ddx3y, compensates for Ddx3x in the developing male neocortex. Using live imaging of progenitors, we show that DDX3X promotes neuronal generation by regulating both cell cycle duration and neurogenic divisions. Finally, we use ribosome profiling in vivo to discover the repertoire of translated transcripts in neural progenitors, including those which are DDX3X-dependent and essential for neurogenesis. Our study reveals invaluable new insights into the etiology of DDX3X syndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms.
Whereas no known living vertebrate possesses gills derived from the jaw-forming mandibular arch, it has been proposed that the jaw arose through modifications of an ancestral mandibular gill. Here, we show that the zebrafish pseudobranch, which regulates blood pressure in the eye, develops from mandibular arch mesenchyme and first pouch epithelia and shares gene expression, enhancer utilization, and developmental gata3 dependence with the gills. Combined with work in chondrichthyans, our findings in a teleost fish point to the presence of a mandibular pseudobranch with serial homology to gills in the last common ancestor of jawed vertebrates, consistent with a gill origin of vertebrate jaws.