Neuronal subtype determined by graded activity of the transcription factor Ascl1

15 February 2013

Researchers at NIMR have shown that neurons can be made different from one another by expressing either high or low quantities of the protein, Ascl1. The research is published in Current Biology.

During the formation of the brain and spinal cord different types of neurons are produced in specific locations. Diffusible signalling molecules control where specific types of neurons are made, by turning on or off the expression of critical genes that regulate transcription within neural progenitor cells. Typically, a small number of these transcription factors act in concert in neural progenitors to make a specific neuronal subtype. By varying the combinations of transcription factors that are activated within the progenitor cell, many different types of nerve cells can be made. However, in certain instances the same combination of factors appears to specify very different types of neuron. Two subpopulations of progenitor cells in the brain and spinal cord make serotonergic neurons and so-called V3 interneurons, respectively, but they express the same combination of transcription factors all of which are essential for the production of both types of neuron.

Precise measurements of the expression of one of these factors, Ascl1, has revealed that it is expressed at a high level in hindbrain progenitor cells and at a low level in the spinal cord progenitors. John Jacob, working in the laboratory of James Briscoe (pictured) in NIMR's Division of Developmental Biology, has collaborated with David Wilkinson’s laboratory in the Division of Developmental Neurobiology, and the laboratories of Dr Ben Novitch in UCLA and Professor Ryo Kageyama in Kyoto University. The researchers used in ovo electroporation, conditional mouse genetics and RNA interference approaches, to show that the spinal cord cells could make either type of neuron, depending on how much Ascl1 they expressed. Moreover, they showed that under physiological conditions, the level of expression of Ascl1 in both progenitor populations is tightly regulated by the signalling molecule retinoic acid acting through the Notch pathway.

During the formation of the brain numerous different types of neurons are produced at specific locations in the nervous system. An enduring model for how this occurs is that extrinsic signals induce qualitative differences in the transcription factor ‘code’ expressed by neural progenitor cells. What we’ve found is that quantitative differences in expression of one of these so-called fate determinants, Ascl1, is also important for neurons to be made different from one another.

James Briscoe

Serotonin, the neurotransmitter made by one of the neuronal subtypes we analysed, has potent effects on nervous system function and is implicated in several common neurological and psychiatric disorders. Therefore tight regulation of Ascl1 is likely to be important in constraining the production of these neurons within a specific location in the brain.

John Jacob

Click image to view at full-size

Unilateral in ovo electroporation of Ascl1, marked by green fluorescent protein (green cells, right panel) in a subpopulation of ventral spinal cord progenitor cells, induces ectopic serotonergic neurones (red cells, left panel; arrows, right panel) that are never normally present in this region of the central nervous system.
'–', control side, '+', electroporated side.

Original article

John Jacob, Jennifer Kong, Steven Moore, Christopher Milton, Noriaki Sasai, Rosa Gonzalez-Quevedo, Javier Terriente, Itaru Imayoshi, Ryoichoro Kageyama, David G. Wilkinson, Bennett G. Novitch, and James Briscoe (2013)

Retinoid acid specifies neuronal identity through graded expression of Ascl1

Current Biology Epub ahead of print. Abstract

 

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