Identification of FoxP circuits involved in locomotion and object fixation in Drosophila
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Abstract
The FoxP family of transcription factors is necessary for operant self-learning, an evolutionary conserved form of motor learning. The expression pattern, molecular function and mechanisms of action of the Drosophila FoxP orthologue remain to be elucidated. By editing the genomic locus of FoxP with CRISPR/Cas9, we find that the three different FoxP isoforms are expressed in neurons, but not in glia and that not all neurons express all isoforms. Furthermore, we detect FoxP expression in, e.g., the protocerebral bridge, the fan shaped body and in motorneurons, but not in the mushroom bodies. Finally, we discover that FoxP expression during development, but not adulthood, is required for normal locomotion and landmark fixation in walking flies. While FoxP expression in the protocerebral bridge and motorneurons is involved in locomotion and landmark fixation, the FoxP gene can be excised from dorsal cluster neurons and mushroom-body Kenyon cells without affecting these behaviors.
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###Reviewer #2:
While this paper develops some useful tools for targeting neurons expressing different isoforms of the FoxP transcription factor, the broad expression of FoxP (~1800 neurons throughout the brain and VNC) makes it challenging to interpret the general motor deficits that result from knocking out FoxP expression during development. The study lacks a structural or physiological link between the low-level genetic manipulations (elimination of FoxP expression) and high-level behavioral phenotypes (abnormal locomotion and landmark fixation).
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###Reviewer #1:
This is an elegant molecular manipulation of the FoxP gene, coupled with anatomical description of the neuronal distribution of isoform expression in the brain and ventral nerve cord of the fly.
Isoform B functional knockouts show behavioral abnormalities in flies' ability to walk toward a dark vertical bar representing naturally attractive landscape features like plant stalks. FoxP isoform B manipulated animals walk slower and are less adept at targeting the dark bar. Knocking out all FoxP isoforms has similar behavioral effects as knocking out FoxP-iB alone.
FoxP is expressed broadly throughout the peripheral and central brain and in the ventral nerve cord, throughout development. Expression within leg motorneurons and the protocerebral bridge of the central complex is required for normal walking visual fixation, which …
###Reviewer #1:
This is an elegant molecular manipulation of the FoxP gene, coupled with anatomical description of the neuronal distribution of isoform expression in the brain and ventral nerve cord of the fly.
Isoform B functional knockouts show behavioral abnormalities in flies' ability to walk toward a dark vertical bar representing naturally attractive landscape features like plant stalks. FoxP isoform B manipulated animals walk slower and are less adept at targeting the dark bar. Knocking out all FoxP isoforms has similar behavioral effects as knocking out FoxP-iB alone.
FoxP is expressed broadly throughout the peripheral and central brain and in the ventral nerve cord, throughout development. Expression within leg motorneurons and the protocerebral bridge of the central complex is required for normal walking visual fixation, which is entirely consistent with what we've been learning about the functional organization of this brain region for spatial navigation.
The problem here is that the conceptual gap between molecular manipulation of the FoxP gene and the behavioral phenotype is wide. Absent any understanding of either the cell physiological mechanisms of action of FoxP, or the function of FoxP-positive neural circuitry involved in the behavior being explored, the advance remains preliminary.
Even in the case where identified neurons that have recently been implicated in bar fixation by walking flies, which the authors demonstrate express at least some FoxP isoforms, broad FoxP knockout had no effect on the behavior. As the work is currently presented, there is not enough resolution between FoxP expression, cell circuit function, and behavior for the work to make a sufficiently compelling case.
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##Preprint Review
This preprint was reviewed using eLife’s Preprint Review service, which provides public peer reviews of manuscripts posted on bioRxiv for the benefit of the authors, readers, potential readers, and others interested in our assessment of the work. This review applies only to version 2 of the manuscript.
###Summary:
The reviewers thought that the work was of quality and that the paper develops some useful tools for targeting neurons expressing different isoforms of FoxP. However, they also felt that there is a conceptual gap between the molecular manipulation of FoxP and the behavioral phenotype, with little understanding of the mechanisms of action of FoxP and of the function of FoxP in the neural circuitry involved in the behavior.
The broad expression of FoxP in ~1800 neurons makes it challenging to interpret the …
##Preprint Review
This preprint was reviewed using eLife’s Preprint Review service, which provides public peer reviews of manuscripts posted on bioRxiv for the benefit of the authors, readers, potential readers, and others interested in our assessment of the work. This review applies only to version 2 of the manuscript.
###Summary:
The reviewers thought that the work was of quality and that the paper develops some useful tools for targeting neurons expressing different isoforms of FoxP. However, they also felt that there is a conceptual gap between the molecular manipulation of FoxP and the behavioral phenotype, with little understanding of the mechanisms of action of FoxP and of the function of FoxP in the neural circuitry involved in the behavior.
The broad expression of FoxP in ~1800 neurons makes it challenging to interpret the motor deficits that result from knocking out its expression during development. Although neurons that express FoxP have recently been implicated in bar fixation, the behavioral phenotype of the FoxP knockout is difficult to interpret. Therefore, the integration of FoxP expression, the function of the circuit involving FoxP and the behavior is not sufficiently clear.
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