Ž . Developmental Brain Research 110 1998 135–158 Interactive report Ontogeny of vesicular monoamine transporter mRNAs VMAT1 and VMAT2 I. The developing rat central nervous system 1 a,2 a ´ b, ) Stefan R. Hansson , Beth J. Hoffman , Eva Mezey a Unit on Molecular Pharmacology, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda MD USA b Basic Neuroscience Program, National Institute of Neurological Disease and Stroke, Bldg 36, 3D10, Bethesda MD 20892 USA Accepted 4 July 1998 Abstract We used in situ hybridization histochemistry to study the expression of the mRNA of the two vesicular monoamine transporters Ž . Ž . VMAT1 and VMAT2 during embryonic and postnatal development of the central nervous system CNS in the rat. In the adult rat, VMAT2 mRNA is present exclusively in monoaminergic cell groups of the CNS and VMAT1 mRNA was reported to be present in the adrenal medulla and certain intestinal epithelial cells. In contrast to the above, the expression of VMAT1 mRNA has previously never been detected in the central nervous system. This study shows the first evidence that both transporter molecules are expressed in CNS during ontogenesis. We here demonstrate four main expression patterns detected during development: 1. VMAT2 mRNA expression in monoaminergic neurons of the brainstem beginning as early as embryonic day E13. 2. Expression of VMAT2 mRNA in all major sensory relay nuclei of central nervous system. 3. Co-expression of VMAT1 and VMAT2 mRNA in most limbic structures, basal ganglia, as well as in some hypothalamic nuclei. 4. Exclusive expression of VMAT1 mRNA in the neocortical subventricular zone, in the amygdala at Ž . Ž . early E15–18 and late P1–P28 timepoints, the granular cell layer of cerebellum, and in several brainstem motor nuclei. Based on their distribution during development we suggest that monoamines, released in a controlled fashion, might affect wiring of sensory and also motor circuits. VMAT1 mRNA expression may reflect a specific effect of monoamines in glial differentiation and cerebellar granule cell migration andror differentiation. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Biogenic amines; Embryonal development; Subventricular zone; Basal ganglia; Sensory nuclei; Limbic system; Hypothalamus 1. Introduction Monoamines and their role in development have been studied extensively. Early mapping of monoaminergic cell groups was made possible by fluorescence techniques de- w x veloped by Falck et al. 13,31,32,36 . Later the rate limit- ing enzymes for the different monoamines have been mapped by immunohistochemistry during pre- and postna- Ž . tal development. Tyrosine hydroxylase TH , which cataly- w x ses the initial step in catecholamine synthesis 8,10,37,38 w x has been well studied during development 3,10,35 . In the ) Corresponding author. Tel.: q1-301-435-5635; Fax: q1-301-435- 5465; E-mail: mezey@codon.nih.gov 1 Published on the World Wide Web on 3 August 1998. 2 On leave from the Division of Molecular Neurobiology, Wallenberg Neurocenter, University of Lund, Sweden. initial pioneering studies Axelrod et al. demonstrated up- w x take of tritiated norepinephrine 9,23 , and in more recent studies the effect of the disruption of the gene encoding w x TH have been demonstrated 42 . This latter study sug- gested that catecholamines might be crucial for survival since 90% of the mutant mice died of cardiovascular failure between embryonic days E11.5 and E15. By admin- istering L-DOPA, the product of TH, the animals were able to survive somewhat longer. This indicates that monoamines are in fact important for proper development and survival of the embryo. After their synthesis, monoamines are packaged and stored in synaptic vesicles by the action of vesicular Ž . transporters VMATs . Two distinct isoforms have been w x w x cloned and named VMAT1 11 and VMAT2 28 . VMAT1 is mainly expressed by chromaffin cells of the adrenal w x medulla 11,12,34,40 and VMAT2 by biogenic amine cells of the adult central nervous system. The two trans- 0165-3806r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. Ž . PII: S0165-3806 98 00104-7