Genetic regulation of neural stem/progenitor cells and neurogenesis in the adult hypothalamus

The hypothalamus is an area of the brain that regulates key physiological functions ranging from mood and sleep to appetite and energy expenditure. Recent work from our lab has shown that new neurons are generated in the hypothalamus of adolescent and adult mice. Intriguingly, these neurons appear to be destined for circuits that regulate appetite and energy expenditure. This raises the interesting possibility that these circuits can be modulated to the benefit of human health. In particular, to preserve the healthy functioning of the brain in aged individuals and tackling eating disorders, such as obesity.
We have discovered that the new hypothalamic neurons arise from a unique population of stem cells, called tanycytes. We have also found that these cells express a very important signaling gene, called Fgf10. Our main objectives are to characterize and understand the function/s of Fgf10 in tanycytes. To meet these objectives, we will use well-characterized tissue culture systems and examine the brains of genetically modified mice, in which the functioning of Fgf10 has been abrogated or elevated. We will also investigate the cohort of genes and molecules that Fgf10 may talk to and interact with to exert its functions.
The generated information will advance our knowledge of brain stem cells and brain function and may well lead to the development of molecular tools to positively modulate brain function.

Until recently, the generation of new neurons in the adult mammalian brain was thought to be restricted to the hippocampal dentate gyrus and the lateral subventricular zone of lateral ventricles, where neural stem cell function has been extensively studied and shown to be regulated by a combination of cell intrinsic and cell extrinsic factors. However, emerging data suggest that new neurons are also generated in postnatal and adult hypothalamus and their prime function is to endow plasticity to neural circuits that regulate energy uptake and expenditure. We have identified the source of these cells as beta tanycytes, a population of radial glial-like cells that occupy the ventral lining of the third ventricle. Very little is known about genes and mechanisms that regulate stem/progenitor cell function in tanycytes, and the steps of adult hypothalamic neurogenesis. To identify these, we will exploit our discovery that in the hypothalamus, Fibroblast growth factor 10 (Fgf10) is uniquely expressed by beta tanycytes. Our objectives are to test whether and how the loss or over expression of Fgf10 affects the ability of beta tanycytes to generate neurospheres in vitro and their ability to divide, survive and generate new appetite/ energy balance regulating neurons in vivo. In a complementary approach, we will search for genes that act downstream of, and the proteins that interact with FGF10 in tanycytes. Combined, these investigations are likely to provide novel inroads into the genetic networks that regulate neural stem cell function in the hypothalamus. Our ultimate goal is to exploit this knowledge to manipulate hypothalamic neurogenesis and preserve its healthy functioning during ageing and prevent or alleviate its malfunctioning which results in eating disorders.

Eating disorders pose a major challenge to human health. At one end of the scale there is a gradual loss of appetite in the elderly exacerbating the effects of age-related decline in these individuals, and at the other there is an alarming rise in the prevalence of obesity, particularly in children. Treatment of obesity and its related syndromes (cardiovascular defects, arthritis and diabetes) has imposed a huge social and financial burden on individuals and health budgets worldwide. The hypothalamus is where external stimuli (hormones and metabolites) converge to regulate appetite and energy expenditure and thus there is an avid search to understand the cellular, molecular and physiological mechanisms through which appetite is normally regulated and can be positively (or negatively) manipulated to meet the above challenges.
Recent exciting discoveries, including those from our own lab, suggests that new neurons are generated in the mammalian hypothalamus by a population of stem/progenitor-like cells termed beta-tanycytes. Moreover, the newly-generated neurons integrate into the appetite/energy balance regulating nuclei. This suggests that the new neurons endow a degree of plasticity and malleability to hypothalamic functions, raising the exciting possibility that hypothalamic neurogenesis can be focally and experimentally manipulated to promote healthy aging in the elderly or to counteract or prevent obesity. To underpin these efforts, in the first instance we need to understand the basic cellular and molecular regulators of neurogenesis in the adult hypothalamus.
This proposal exploits our discovery that a key member of the fibroblast growth family, namely Fgf10, is expressed uniquely by beta tanycytes, suggestive of important regulatory roles in their maintenance and neurogenic capacity. We now wish to understand the function/s of Fgf10 and use it as bait to dissect the genetic network that regulates tanycytes and adult hypothalamic neurogenesis.
Tanycytes also have important physiological functions, such as the transport of ions and metabolites into the parenchymal cells and so our studies could additionally reveal a novel role/s for Fgf10 in these crucial processes.
Combined, this research will significantly advance our understanding of a unique population of neural stem/progenitor cells in the brain. It may also provide important breakthroughs in preventing or alleviating anorexia in the elderly and obesity in the wider population.