"Homeoprotein (HP) signaling designates the ability of HP transcription factors to transfer between cells, thus acting as signaling molecules. We will investigate several properties of this novel signaling pathway in the CNS and how it can shed light on brain development and physiology, also neurological and psychiatric pathologies. The studies will concentrate on 4 HPs (Engrailed1/2, Otx2 and Pax6) illustrative of the HP family and of high physiological interest. Mouse lines will be developed in which the extracellular expression of single chain antibodies against these HPs can be induced at specific places and times, allowing us to follow the consequences of neutralizing extracellular HPs while preserving their cell autonomous functions. With this tool (and others) we shall study if (and how) HP transfer regulates boundary position in the neuroepithelium and direct cell/axon migration and guidance. In postnatal development, we will dissect how Otx2 regulates the opening, closure and reopening of critical periods in the cortex and controls the behavior of neuronal networks throughout life. Also in the adult we will follow how HPs regulate the physiology and survival of distinct neuronal groups, including midbrain dopaminergic neurons. We shall analyze the physiological interactions between HPs and classical signaling molecules and identify HP targets, in particular those regulating the cell energy metabolism, and explore their ability to modulate the epigenetic state of the chromatin. Using Otx2 and Engrailed as baits, we shall identify the complex sugars with which they interact at the cell surface to get an entry into the ""sugar code"" that confers specificity to HP capture by distinct cell populations. This project should identify new HP functions and highlight them as part of a major mode of signal transduction in the developing and mature CNS. It is expected that this will modify the way we look at many developmental, evolutionary and physiological mechanisms."