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Co-authors Tehyen Chu and Sam Kunes

One of a cell’s fundamental tasks is to deliver its synthetic products to subcellular locations appropriate for their function.  Nowhere is this more apparent than in the nervous system, where highly specialized functions are carried out in subcellular compartments such as the axon, dendrite and synapse. Such localization is also found in development, where morphogens are delivered in precise and differing concentrations across fields of receptive cells, as is required for assigning different cell fates.  To achieve this precision, the ‘signaling cell’ will often release a morphogen from a particular subcellular location, such as the apical or basal pole, or an appendage such as a cytoneme or axon. From such a specialized point of release, a morphogen encounters unique environments that determine its distribution and shape its developmental activity. This is the case for the morphogen Hedgehog (Hh), a key determinant of pattern formation in tissues as diverse as wings, legs, guts and brains.

The cover image is a confocal micrograph of the developing retina and brain of Drosophila. Photoreceptor neurons that differentiate in the retina (top left)send their axons (labeled green) through the optic stalk into the developing optic lobe (bottom). In the brain, the photoreceptor axons deliver the Hedgehog protein, which induces the differentiation of post-synaptic lamina neurons (indicated by Dachshund (blue) and Elav (red) expression). Targeting Hedgehog to the brain requires a phylogenetically conserved C terminal amino acid motif.

In the developing Drosophila visual system, the photoreceptor neurons synthesize Hedgehog and distribute it to two receptive fields located at the opposite ends of the neuron. These fields become the release points of Hh. On the apical side, Hh is released into the developing eye to propagate the wave of ommatidial differentiation (the forming of more units of the compound eye), generating more photoreceptor neurons. On the basal side, Hh is transported along the photoreceptor axons and released by the growth cones to induce the post-synaptic neurons that form the first-stage neural circuit for motion detection. This bi-directional delivery of Hedgehog coordinates and controls the development of the two receptive fields, yielding pre- and post-synaptic partners in proper time and number. How is Hh partitioned for release in the right amounts from the opposite ends of the photoreceptor neuron?

In our latest work, published in the journal Developmental Cell, we show that targeting of Hedgehog to axons, growth cones and synapses relies on a phylogenetically conserved amino acid motif located at  the Hedgehog C-terminus. Conversely, the Hh N-terminus harbors apical targeting information. Competition (or perhaps collaboration) between these signals partitions Hedgehog between the eye and brain, balancing photoreceptor and post-synaptic neuronal development. When this mechanism is disturbed, by mutating the ‘axon-targeting’ motif for example, the balance of eye and brain development becomes aberrant. Vertebrate Hedgehog family members also undergo axon transport in order to act as long-distance developmental regulators. Thus we suppose that the axon-targeting motif is part of a conserved machinery designed to distribute this morphogen for its developmental functions. Our next step will be to identify the molecular components of the distribution apparatus.

View Sam Kunes’s Faculty Profile