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GTP cyclohydrolase I (GTPCH) is the first and rate-limiting enzyme in the tetrahydrobiopterin (BH4) biosynthetic pathway. BH4 is the essential cofactor for the pterin-dependent monooxygenases which include tyrosine and tryptophan hydroxylase, enzymes that are rate limiting in the biosynthesis of catecholamines and indolamines. BH4 is also required as a cofactor for the family of nitric oxide synthases1,2. We have obtained a clone for GTPCH based on the recently published full-length cDNA encoding GTPCH from rat liver3,4. The in situ hybridization technique was used to study the cellular localization and the relative levels of expression of GTPCH mRNA in the rat brain.

The development of the concept of chemical transmission at the synapse and its application to the central nervous system has resulted in remarkable advances in our understanding of brain structure, function, and pathology. Among these, it has provided a basis for characterizing neuronal systems other than on morphological criteria. The utility of this characterization is best exemplified by our current knowledge of catecholamine and indolamine neuron systems in the mammalian brain. The presence of an indolamine (5-hydroxytryptamine, or serotonin) and catecholamines (norepinephrine, dopamine) in brain in a nonuniform pattern was first established 20 years ago (Twarog and Page, 1953; Amin et al., 1954; Bogdanski et al., 1957; Bertler and Rosengren, 1959) and led to the proposal that these compounds serve as chemical mediators of synaptic transmission (Amin et al., 1954; Vogt, 1954; Brodie and Shore, 1957). Subsequent studies in which brain amine content was analyzed following placement of localized destructive lesions indicated an association of specific neuron systems, particularly the medial forebrain bundle, with these putative neurotransmitters (Heller et al., 1962; Heller and Moore, 1968). It was not until the development of a specific and sensitive histochemical procedure for the intraneuronal localization of indolamines and catecholamines, the Falck-Hillarp method (Falck et al., 1962; Carlsson et al., 1962; Falck, 1962; Corrodi and Jonsson, 1967; Bjorklund et al., 1972), however, that significant advances were made in analyzing the specific neuronal systems which produce serotonin and catecholamines in brain.

Neural growth and differentiation is regulated by genetic and epigenetic factors. Although genetic regulation is only recently beginning to be explored, intrinsic epigenetic control of neural growth has been the focus of research for several investigators. The regulatory role of hormones such as thyroid hormones and steroid hormones in neural growth and differentiation has been well documented. More recently, we (Vernadakis and Gibson, 1974) and others (Lauder, 1979) have proposed that neurohumor substances such as acetylcholine, catecholamines and indolamines are involved in cellular processes including neuro-genesis before their involvement in neurotransmitter processes. As it has been abundantly demonstrated with hormones, it is probably the combination of actions and interaction of several neurohumor substances that influence cellular growth. Moreover, neuronalglial interrelationships and the influence of neurohumor substances thereon are important factors in neural growth and differentiation. Lauder and associates will discuss in this symposium their work with serotonin on neurogenesis. We will discuss primarily the role of norepinephrine in neural growth. We have used the chick embryo as an animal model to study maturational processes at the organismic level and neural culture to characterize differential responses of neurons and glial cells to neurohumor substances.

The regeneration of the arm of the crinoid Antedon mediterranea has been studied by means of LM, TEM, and SEM techniques as regards the development of both the external form and the internal anatomical organization. According to the timing and the modalities of development of the different structures and their reciprocal interactions, three main stages can be recognized in the morphogenesis of the whole arm: 1) a coelom-dependent stage, 2) a nervous system-dependent stage and 3) a skeleton-dependent stage. Moreover, using histofluorescence and immunohistochemical methods to visualize catecholamines and indolamines, it has been possible to reveal the presence of dopamine and serotonin and follow the fluctuations and the different involvements of these neuro-trasmitters during the regeneration process.