Sonic hedgehog-dependent recruitment of GABAergic interneurons into the developing visual thalamus

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Axons of retinal ganglion cells (RGCs) play critical roles in the development of inhibitory circuits in visual thalamus. We previously reported that RGC axons signal astrocytes to induce the expression of fibroblast growth factor 15 (FGF15), a motogen required for GABAergic interneuron migration into visual thalamus. However, how retinal axons induce thalamic astrocytes to generate Fgf15 and influence interneuron migration remains unknown. Here, we demonstrate that impairing RGC activity had little impact on interneuron recruitment into mouse visual thalamus. Instead, our data show that retinal-derived sonic hedgehog (SHH) is essential for interneuron recruitment. Specifically, we show that thalamus-projecting RGCs express SHH and thalamic astrocytes generate downstream components of SHH signaling. Deletion of RGC-derived SHH leads to a significant decrease in Fgf15 expression, as well as in the percentage of interneurons recruited into visual thalamus. Thus, our findings identify a morphogen-dependent neuron-astrocyte signaling mechanism essential for the migration of thalamic interneurons.

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  1. Evaluation Summary:

    This paper proposes a novel mechanism used by the visual system to recruit interneurons into the visual thalamus. The primary claims that retinal ganglion cell axons secrete Shh in the visual thalamus that induces FGF15 expression by astrocytes, that then attract interneurons are sound. Because Shh signaling, interneuron migration, and astrocyte functions are studied by a large number of neuroscientists this study will have a high impact on the field.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

  2. Reviewer #1 (Public Review):

    In this manuscript, Somaiya and colleagues make an interesting contribution to our understanding of the development of the visual system. The group has previously found that the presence of retinal ganglion cell (RGC) axon terminals in the lateral geniculate nucleus (LGN) promotes the migration of GABAergic interneurons into the LGN by stimulating FGF15 expression in astrocytes. The goal in the current paper was to test how RGCs promote this process. The authors suggest a model in which neuronal activity is not required for this, but rather Sonic Hedgehog (SHH) produced by RGCs and released from axon terminals can be received by astrocytes to stimulate FGF15 production, leading to interneuron migration.

    They present three major findings in support of this model:

    1. Transgenic expression of tetanus toxin in RGCs to prevent synaptic activity did not prevent interneuron migration into the LGN.
    2. RGCs expressed SHH at the relevant developmental time point, and astrocytes within the LGN expressed Ptch1 (the canonical SHH receptor) along with other SHH signaling components.
    3. Disruption of SHH - either in all neurons or in RGCs - prevented astrocytic FGF15 expression and interneuron migration into the LGN.

    In general, the manuscript was well-written and carefully reasoned. The authors concede that a key experiment to close the circle in their model could not be performed for technical reasons, namely astrocyte-specific disruption of Ptch1. Accepting this limitation, the expression analyses for SHH signaling components using RNAscope and a genetically encoded reporter were enough to convince this reviewer that astrocytes were the main cell type in the LGN capable of responding to SHH signal. However, there was an important control missing from the SHH experiments, as the authors did not show that the RGC axons successfully targeted to the LGN in the absence of SHH. This leaves open alternative explanations involving other axon-derived molecules.

  3. Reviewer #2 (Public Review):

    In this study Somaiya et al. identify a molecular mechanism used to guide Gad1 expressing cells into the vLGN and dLGN during mouse development. It has been shown previously that RGC inputs are required for these areas to recruit these interneurons and that thalamus derived astrocyte-derived FGF15 expression is dependent on RGC input. Here the authors perform a series of experiments that demonstrate that RGC derived Shh is important for this induction and therefore the recruitment of interneurons to the visual thalamus. Overall these experiments are well thought out and support the author's hypothesis. Because Shh signaling is important for many developmental processes, this result should be of wide interest to the scientific community.

    Strengths include the well-thought-out logic and presentation of the experiments designed to test their hypotheses, and the use of transgenic mice to block activity or remove Shh in vivo, and the significant changes seen in the mutants. A minor weakness is that evidence showing that all activity is blocked in the retina of the TeNT mice is not convincing.