New role of a key gene regulator which determines the fate of neurons in the developing brain


02 Jun 2017

New role of a key gene regulator which determines the fate of neurons in the developing brain

 

By Dr Bhavana Muralidharan, Early Career Fellow

TIFR Mumbai

The cerebral cortex is a complex brain structure that processes higher functions in distinct regions.  It is the seat of sensory perception, decision-making, language and memory. For the cerebral cortex to function normally, a precise development of circuitry is essential, which entails a diverse array of neuronal subtypes being generated in a sequential manner. Perturbations of this process can lead to a range of neurological diseases and disability.

Transcription factor Lhx2 regulates fundamental steps in the development of the cerebral cortex, including neurogenesis and cell fate specification.

We have recently shown that Lhx2 regulates the numbers of a very specific class of cortical neurons, which project to sub-cerebral regions in the brain including the spinal cord and are called the sub-cerebral projection neurons (SCPNs). It does so by binding to sequences in the genome, which regulate the expression of two transcription factors Fezf2 and Sox11, which are critical for the generation of the SCPNs in the developing brain.

Loss of Lhx2 leads to an increase in SCPNs and overexpression of Lhx2 leads to a decrease in SCPNs, thereby making Lhx2 as a necessary and sufficient regulator of the production of this particular class of cortical neurons.

We also provide mechanistic insight into how Lhx2 could execute the suppression of its target genes. We show that Lhx2 interacts with components of the chromatin remodeling complex NuRD. The role of this complex is to control gene activity by altering the accessibility of the chromatin to transcriptional factor complexes. We show that loss of Lhx2 leads to an increase in the active marks on the chromatin of Fezf2 and Sox11, increases their expression within a day of Lhx2 removal, and causes a striking increase in sub-cerebral neuronal numbers seen in maturity.

This is a novel function of Lhx2, as a key regulator of neuronal subtype identity in the neocortex. Overall, our study provides mechanistic insight into how the neurons responsible for cortical circuitry are generated in appropriate numbers and distinct subtypes during cortical development and can be used as a framework to study what goes wrong in developmental disorders like autism where the precise numbers of these neurons are altered. 

Lhx2 interacts with the NuRD complex and regulates cortical neuron subtype determinants Fezf2 and Sox11. Muralidharan B, Khatri Z, Maheshwari U, Gupta R, Roy B, Pradhan S.J, Karmodiya K, Padmanabhan H, Shetty A, C. H. Balaji, Kolthur-Seetharam U, Macklis J.D, Galande S, Tole S.  Journal of Neuroscience. January 2017