WNT signaling in hypothalamic neural progenitor differentiation

Postdevelopmental neurogenesis is a general phenomenon found in all vertebrate brains, and is of potential therapeutic interest for the treatment of human degenerative diseases. It is known that the rostral migratory stream (RMS) and the subgranular zone (SGZ) of the dentate gyrus maintain constitutive neurogenesis in the adult mammalian brain, and recent preliminary studies have shown that a lower rate of adult neurogenesis persists in previously uncharacterized regions of the brain including hypothalamus. The key regulators for the differentiation of embryonic/adult neural stem cells have been intensely studied, but their precise roles remain highly controversial. When I initially began this project, the Wnt signaling pathway is known to play a significant role in developmental neurogenesis, and Wnt activity is evident in several regions of the brain that maintain constitutive neurogenesis. However, the specific role of Wnt signaling in zebrafish hypothalamic neurogenesis was unknown. Therefore, I investigated the precise pattern and function of hypothalamic Wnt activity, and I performed a complete functional analysis in the zebrafish and adult mouse hypothalamus. My work characterized Wnt expression patterns in the zebrafish and adult mouse hypothalamus, and uncovered two major stages of neurogenic development in the zebrafish hypothalamus: 1) Wnt activity is first required for the proliferation of unspecified hypothalamic progenitors in the embryo; 2) Wnt activity is required again, transiently, for the differentiation of neural progenitors throughout the life of the differentiation of neural progenitors throughout the life of the animal. In this second stage, our findings suggest that Wnt activity is required for the differentiation of neural progenitors, and is subsequently down-regulated to promote the transition from progenitor to precursor and finally, postmitotic neuron. Additionally, I discovered that Wnt signaling plays a conserved role in the differentiation of Wnt-responsive neural progenitors arising from the parenchymal zone in the adult mouse hypothalamus, and in inhibiting the differentiation of tanycytes arising from ventricular progenitors in both the mice and zebrafish hypothalamus. Thus my studies have established the vertebrate hypothalamus as a model for Wnt-regulated postembryonic neural progenitor differentiation, and have demonstrated that the general existence and function of Wnt signaling in this tissue is evolutionarily conserved across both developmental stages and species.