Friedrich Nietzsche was horrified by the concept of eternal recurrence, the possibility that the universe repeats itself infinitely in structure and experience. As a solution to this existential burden, Nietzsche proposed that man abandon idealism and embrace amor fati – a love of fate. Now, a recent paper from Richard Mann's lab at Columbia University has reclaimed human idealism by re-examining the fundamental structure of fate itself. Specifically, they asked the question: given the extreme diversity of neurons in the brain, what factors determine a neuron's unique and highly specialized fate?

Jonathan Enriquez and colleagues addressed this question by studying the development of motor neurons in the Drosophila ventral nerve cord, a region of the fly's central nervous system analogous to the vertebrate spinal cord. The ventral nerve cord is home to the motor neurons that control movements of the leg – each of the fly's six legs contains 14 muscles, which are wired up to approximately 50 motor neurons. Although each of these leg motor neurons is unique in structure and function, most of them develop from just two neuronal stem cells, or neuroblasts. Thus, the same stem cell gives rise to a diverse but manageable group of neuronal cell types. The fact that each of these motor neurons is uniquely identifiable in every fly suggests that their development is under careful genetic control.

To identify the genetic factors that determine a motor neuron's identity, Enriquez and colleagues searched for expression of unique transcription factors – proteins that regulate gene expression by binding to specific DNA sequences. Within the fly genome, there are ∼750 genes that can be differentially spliced to produce ∼2000 unique transcription factors. Using antibodies against several hundred of these transcription factors, the authors were able to identify genetic signatures for each of the different motor neuron types generated by a particular neuroblast. They found that each neuron expressed a unique, though overlapping, combination of transcription factors. This result suggests that parental stem cells assign functional identity to their daughter neurons using a combinatorial code of transcription factors, which is then expressed throughout the neuron's life – from stem cell differentiation into adulthood.

Although the existence of a combinatorial code is interesting, a deeper question is how the individual elements within the code contribute to a neuron's fate. Does the development of a neuron's morphological identity require a full complement of transcription factors? Or does each transcription factor contribute in some marginal way to a neuron's final identity?

The authors investigated the nature of the combinatorial code in two elegant ways. First, they removed a single transcription factor (called pb) from the code. This manipulation affected only those motor neurons that normally express pb, by altering both their dendritic and axonal morphology. Second, they expressed pb in a separate neuroblast, which does not normally express this transcription factor. Overexpression caused these motor neurons to acquire some morphological characteristics of pb-expressing neurons, though these neurons retained many aspects of their original identity.

Overall, these experiments demonstrate that each transcription factor instructs the development of specific morphological characteristics. Collectively, the ensemble of transcription factors specifies a unique morphological identity for each neuron. These results point to a general mechanism for producing morphological diversity among neurons. In addition, they suggest that our world may be just as eternally predetermined as Nietzsche imagined, but it still feels good to have cracked a piece of the underlying code.

References

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