UCLA

The central nervous system (CNS) is a very complex and highly organized structure. In the beginning the CNS is a sheet of cells. Over time external cues encourage this sheet to become a tube and from this tube an abundance of cell types are generated. These cells then migrate out, establish contacts with other cells, and form functional circuits. Given the complexity of the CNS, one of the fundamental goals of developmental neurobiology is to understand how this wealth of cellular diversity is generated and organized given the initial guidance of just a few signaling cues. Through the work of many groups, the emerging solution to this unbalanced equation appears to be signaling pathway interactions. To address this we focused our study on the roles and interactions of two major developmental signaling pathways: Notch and Sonic hedgehog (Shh). In the developing CNS, the major role of Notch signaling is progenitor maintenance and the major role of Shh signaling is progenitor patterning. However, when studied together, we observed that Notch signaling was able to modulate a progenitor cell’s response to Shh and in doing so influenced cell fate choices made within the developing spinal cord. Interested in these initial findings, we wanted to study other functions of Notch signaling. In a second study we observed that interactions between Notch and retinoic acid (RA) signaling contributed to neuronal diversity within the caudal hindbrain and rostral spinal cord. Then, in a third study, we observed that Notch signaling maintained apical cell contacts within the developing brain. Collectively, this work illustrates that, within the context of neural development, Notch signaling has multiple functions and this functional diversity is largely facilitated through interactions with other signaling pathways. While the functions of Notch signaling were enriched by pathway interactions, we also took a closer look at the factors that influence Shh signaling activity. In a final study we show that Shh signaling activity can be also be modulated through the protein kinase A (PKA)-direct and PKA-indirect downstream phosphorylation of Gli proteins, bifunctional transcriptional effectors of Shh signaling activity.