The Hunchback temporal transcription factor determines motor neuron axon and dendrite targeting in Drosophila

Background:

During development, diverse populations of cells are produced from identical progenitors by responding to a pattern of spatial and temporal cues. These cues can be intrinsic or extrinsic. The Drosophila nervous system is an excellent model to study the patterns that lead to cellular diversity as each neuronal progenitor (neuroblast; NB) produces a specific lineage of cells with a stereotyped morphology and molecular identity. It is known that as the neuroblasts divide (giving rise to one differentiated neuron and one neuroblast), the transcription factors (TFs) expressed in the neuroblast change. Without this temporal change in TF expression, the neuroblasts do not give rise to the appropriate differentiated neurons. The overarching question of this paper is: how is time used to specify cell identity? In other words, are the properties of specific cells determined by temporal TFs (intrinsic temporal cues) or by birth order regardless of temporal TF expression (extrinsic temporal cues or an internal timer)? To answer this, Seroka & Doe used the NB 7-1 lineage which gives rise to five neurons (U1-U5) with distinct morphological and molecular characteristics. They tested whether intrinsic temporal identity or birth order gives rise to these characteristics by ectopically expressing the Hunchback (Hb) TF in late born neurons and assessing molecular markers, axonal targeting, and dendritic targeting.

 

Key findings:

1. Timing of projection extension is dependent on birth order. Early born neurons send out projections before late born neurons regardless of intrinsic expression of Hb.
2. Molecular identity depends on intrinsic temporal cues, not birth order. Late born neurons ectopically expressing Hb express early born markers.
3. Dendritic and axonal targeting is determined by intrinsic temporal identity, not birth order. Late born neurons ectopically expressing Hb project to the targets of early-born neurons.

Conclusions and Future Directions:

Seroka and Doe show that ectopic expression of an early temporal TF is sufficient to replicate U1/2-like characteristics (ie. molecular identity, dendritic targeting, and axonal targeting) in late born neurons. They therefore conclude that the influence of intrinsic temporal cues outweigh that of birth order in specifying the U1-U5 neurons. Birth order encodes temporal information because early and late born neurons may be exposed to different extrinsic cues at critical time points. There is also evidence that cells may have an internal timer that triggers events in reference to the time of differentiation. Based on this work, however, it appears that temporal TFs have a larger influence on cellular identity than birth order. Future work will look at the downstream genes that are regulated by Hb and how these genetic changes specify axonal and dendritic targeting.

Why I like this preprint:

The original work from Chris Q. Doe that characterized the temporal TFs that pattern Drosophila neuroblasts was done over a decade ago. Current work in the Doe lab, including this paper, is now aiming to understand the mechanisms by which these temporal TFs specify cell type. Specifically, Seroka & Doe break down the components of temporal patterning, asking questions about what characteristics of cellular identity and morphology are determined by intrinsic temporal cues.

Questions for the authors:

1. Are ectopic early born neurons functional? How could you test this in your system?
2. Along the same lines, how do you explain the strange morphology of the ectopic early born neurons? They appear to have similar targets but the morphology is not identical to that of the actual U1/2 cells.
3. Do you think that this finding (ie. that intrinsic temporal cues outweigh extrinsic ones) is valid for other lineages in the fly nervous system? Within other cell types?

Note: This preprint was recently published in Development. Find the article here.

Tags: dendrite morphology, heterochronic, hunchback, larval locomotion, motor circuits, motor neuron, neural circuits, temporal identity, temporal transcription factors

doi: https://doi.org/10.1242/prelights.10105

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