Transcriptional regulation of early cerebral cortex development
The cerebral cortex is the most complex structure in the mammalian brain and the major site of our higher cognitive functions. It is made up of hundreds of distinct neuronal cell types organized into specific layers and areas. During cortex development, progenitor cell proliferation has to be tightly controlled and coordinated with differentiation, but how this is achieved remains poorly understood. It is known that transcription factors are involved, but the mechanisms by which they operate and interact with each other is largely unknown. Elucidating these mechanisms is essential to understand the function, evolution and disorders of the brain.
Dmrt5/Dmrta2 and Dmrt3 are zinc finger transcription factors strongly expressed in a similar graded manner in cortical progenitors that we have identified as key regulators of the growth and patterning of the mouse cerebral cortex. In humans, mutation in Dmrt5 have been associated with microlissencephaly. Despite their importance in corticogenesis, their mechanisms of action remain unknown. Our current work aims to better understand how they function together and interact with other cortical factors in the definition of the dorsal compartment of the telencephalon from which the cerebral cortex develops and how they contribute later to the delicate balance that control cortical progenitor maintenance and cell cycle exit/differentiation that is pivotal for proper brain development. Results of our work may uncover novel essential aspects of the molecular mechanisms of early cortical development and provide explanations to the microcephaly caused by Dmrt5 deficiency in man.
Epigenetic control of pain-sensing neuron differentiation and pain perception
The detection of noxious or damaging stimuli is an ancient process that alerts living organisms to environmental dangers. Harmful stimuli activate receptors on specific sensory neurons called nociceptors, which mediate information transfer via the spinal cord to higher order processing centers resulting in protective behaviors and awareness of pain. Erroneous activation of the pain-sensing system, as in chronic or neuropathic pain, represents a major health burden with insufficient treatment options. In a recent study on genetic disorders rendering individuals unable to feel pain, several mutations have been identified in a novel candidate disease-causing gene, PRDM12 (Chen et al., Nat. Genet., 2015).
Prdm12 encodes an evolutionarily conserved zinc finger transcription factor that is strongly expressed in the developing and adult nervous system, including in the dorsal root ganglia that contain the cell bodies of the somatosensory neurons. Recent work of the laboratory has shown that in sensory ganglia Prdm12 is specifically expressed in the nociceptive lineage and that it is essential for their development and survival mainly because it is required for the initiation and maintenance of NTRK1, the gene encoding the TrkA receptor that binds to nerve growth factor (NGF) (Desiderio et al., Cell Reports 2019). How Prdm12 operates in somatosensory progenitors to regulate TrkA expression and promote a nociceptor fate is currently under investigation.
Besides, our data indicate that Prdm12 remains strongly expressed in the different types of mature nociceptors in head and trunk ganglia postnatally, suggesting that it might also influence nociceptor function at adulthood and may constitute a new target for the development of novel pain therapeutic strategies. This hypothesis is currently also studied the laboratory.