Research from the laboratory of Pierre Vanderhaeghen from the Universite’ Libre de Bruxelles has provided a new perspective on brain development and neural stem cell biology.
The cerebral cortex is the most complex structure in the brain. It is the seat of such higher cortical functions as consciousness, learning and memory, emotion, motor control, and language. To execute these functions, the cerebral cortex is composed of an array of cortical neurons, and these cells are adversely affected in cases of neurological or even psychiatric disorders.
According to work from Vanderhaeghen’s laboratory, a gene known as BCL6 is a key element in the development of cortical neurons during development. BCL6 acts as a transcription factor, which is to say that it plays a role in gene expression. In the case of BCL6, this gene product prevents gene expression (functions as a repressor). In the immune system, BCL6 is made in antibody-producing cells (B cells) and it controls the response of B cells to a signaling protein called Interleukin 4 (IL-4). IL-4 drives the differentiation of B cells into antibody-making plasma cells and drives the maturation of plasma cells into those that make distinct types of antibodies. Even more interestingly, BCL6 is frequently abnormal in a blood cancer known as diffuse large B cell lymphoma (DLBCL),
Two members of Vanderhaeghen’s lab discovered BCL6 in a search for genes that modulate the production of new nerve cells from mouse embryonic stem cells. If they overexpressed BCL6 in neural stem cells made from mouse embryonic stem cells, these stem cells transformed en mass into cortical neurons. Because BCL6 is normally known for its role in blood cancers (lymphomas), this BCL6-medicated function was a complete surprise.
Because data from overexpression studies is always suspect without verification, Vanderhaeghen and his colleagues used mouse genetics to confirm the role of BCL6 in the production of cortical neurons. Vanderhaeghen’s team made mutant mice embryos that had lost a functional copy of the BCL6 gene. When these mice developed to the fetal stage, it was clear that they had small cerebral cortexes that consisted of far fewer cortical neurons. Therefore, BCL6 overexpression increases cortical neuron production and the absence of it decreases cortical neuron production. This certainly confirms the role of BCL6 in cortical neuron development.
Next, Vanderhaeghen’s lab determined how BCL6 was influencing the development of cortical neurons. A protein that is encoded by the Notch gene are essential in the self-renewal of neural stem cells. BCL6 works with another protein called SIRT1 to repress the Notch pathway, and this repression moves the progeny of neural stem cells to differentiate into cortical neurons.
Because cortical neurons are the main entities affected by neurological and psychiatric disorders, this understanding of cortical neuron development might provide insights into inherited forms of dementia, behavioral problems or other types of neurological problems. Also, Vanderhaeghen’s work bring together three major players involved in cancer BCL6), aging, Alzheimer’s disease, metabolism and diabetes (SIRT1), and brain and heart development and cancer (Notch). Because these three genes were not know to interact with each other prior to this work, Vanderhaeghen’s findings have opened up a new avenue of possible targets for therapies and model systems for understanding stem cell renewal and differentiation.