En1 and Wnt signaling in midbrain dopaminergic neuronal development

The mesodiencephalic dopaminergic (mdDA) system has been the focus of intense scientific research due to its involvement in numerous behavioral and neurological disorders and thus its clinical relevance. The neurotransmitter dopamine (DA) is present in different areas of the brain, such as the hypothalamus, the olfactory bulb and the mid-forebrain. In this last area, mdDA neurons are the main source of dopamine in the mammalian central nervous system (CNS), attributable to two ventral groups of neurons: the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) [1-3]. The main innervation targets of mdDA neurons are the basal ganglia. The neurons of the SNc innervate the dorsolateral striatum and caudate putamen forming the nigrostriatal pathway. Neurons of the VTA project to the ventral striatum (nucleus accumbens, amygdala and olfactory tubercle) as part of the mesolimbic system and establish additional ascending connections to the prefrontal cortex forming the mesocortical system. These ventral midbrain nuclei modulate specific brain functions according to its distinct projection fields. The SNc is involved in the control of voluntary movement and body posture, and its selective degeneration leads to Parkinson's disease (PD) [4,5]. The mesocortical and mesolimbic systems, on the other hand, are involved in the modulation and control of cognitive and emotional/rewarding behaviors, and their dysfunction is involved in the pathogenesis of various affective disorders, such as addiction [6-8], depression [9] and schizophrenia [10,11]. Drug abuse, depression and PD constitute highly common health disorders, which explains the intense research in recent years on the mechanisms and factors involved in the generation and survival of mammalian mdDA neurons.The development of an organ, such as the midbrain, implies the sequential occurrence of developmental cascades over time, while these might overlap in time and space [12-14]. During early neuronal indu