Zebrafish study uncovers spatial cues that shape neuron diversity beyond gene expression microbiologystudy

Max Planck Institute for Biological Intelligence researchers have identified over 60 transcriptomic neuron types in the zebrafish optic tectum with nearly identical gene-expression profiles yet very different functions and shapes, demonstrating that spatial positioning influences neuronal function and morphology.

The findings challenge traditional assumptions that neurons of the same transcriptomic type share identical shapes and responses.

In fish, the optic tectum forms the roof of the midbrain. The zebrafish optic tectum processes visual inputs and other sensory information, mapping them topographically over the tectum, setting the locations of objects and events in a body-centered space.

While previous research has described specialized subregions within this map, the relationship between neuronal transcriptomic identity and function remained unclear.

In the study “Transcriptomic neuron types vary topographically in function and morphology,” published in Nature, single-cell RNA sequencing was used to profile tectal neurons six to seven days after fertilization.

Researchers analyzed 45,766 cells and identified 66 distinct transcriptomic neuron types (t-types). Based on differential gene expression, these t-types were further categorized into 33 excitatory and 33 inhibitory subtypes. Multiplexed in situ hybridization and two-photon calcium imaging were used to examine the spatial organization, morphology, and visual response properties of these neurons.

Findings revealed that neurons sharing transcriptomic profiles often displayed diverse morphologies and functional responses depending on their position within the tectum. Certain t-types were distributed along specific molecular layers, with inhibitory and excitatory neurons segregated into deep and superficial regions.

Neurons within the same t-type exhibited varied response profiles to visual stimuli, such as looming threats and moving dots, depending on their precise location.

Sparse neuronal labeling and tracing confirmed that neurons of the same t-type could form different projection patterns and synaptic connections, further emphasizing the role of spatial and developmental factors in determining neuronal function.

The study suggests that external cues, including morphogens and synaptic environment, influence the differentiation and specialization of tectal neurons beyond their genetic identity.

A News and Views commentary, “Does gene expression always reflect function?” by M. Neşet Özel & Claude Desplan, also published in Nature, further underscores this study’s central insight that transcriptomic profiles alone do not always dictate a neuron’s functional and morphological identity.

Although neurons in the same “t-type” share core genetic markers, they can diverge in their responses and shape if they reside in different regions of the optic tectum. This spatial differentiation may be driven by local constraints—such as a neuron’s potential synaptic partners, axon-guidance cues, and other extrinsic factors, rather than by stable changes in gene expression.

As Özel and Desplan point out, the Max Planck study raises a broader challenge in neuronal classification in how to reconcile gene-expression data with the reality that phenotypic diversity often emerges from a combination of intrinsic and extrinsic factors.

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