Zinc Uptake and Storage During the Formation of the Cerebral Cortex in Mice Jessy Hasna 1 & Sylvain Bohic 2 & Sophie Lemoine 3 & Corinne Blugeon 3 & Alexandre Bouron 1,4 Received: 17 January 2019 /Accepted: 20 March 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract The cerebral cortex (or neocortex) is a brain structure formed during embryogenesis. The present study seeks to provide a detailed characterization of the Zn homeostatic mechanisms during cerebral cortex formation and development. To reach that goal, we have combined high-throughput RNA-sequencing analysis of the whole murine genome, X-ray fluorescence nanoimaging (XRF), inductively coupled plasma-atomic emission spectrometry (ICP-AES), and live-cell imaging of dissociated cortical neurons loaded with the Zn fluorescent probe FluoZin-3. The transcriptomic analysis was conducted from mRNAs isolated from cortices collected at embryonic (E) days 11 (E11), E13, and E17 and on postnatal day 1 (PN1) pups. This permitted to characterize the temporal pattern of expression of the main genes participating in the cellular transport, storage, and release of Zn during corticogenesis. It appears that cells of the immature cortex express a wide diversity of actors involved in Zn homeostasis with Zip7, SOD1, and metallothioneins being the most abundant transcripts throughout corticogenesis. The quantification of total Zn with XRF and ICP-AES reveals a reduction of Zn levels. Moreover, this is accompanied by a diminution of the size of the internal pools of mobilizable Zn. This study illustrates the tight temporal and spatial regulation of Zn homeostasis during cerebral brain development. Keywords Brain development . Zinc . Corticogenesis . Transcriptome . RNA-seq Introduction The cerebral cortex, or neocortex, is a brain structure consisting of six superimposed layers of neurons, mainly of glutamatergic type. Its formation, called corticogenesis, oc- curs during embryogenesis and requires synchronized and regulated sequences of cell proliferation, migration, morpho- logical differentiation, and synaptogenesis [1, 2]. At early embryonic stages, around embryonic day 9 (E9), the cortical wall mainly consists of a layer of proliferative neuroepithelial progenitor cells forming the ventricular zone and producing the first post-mitotic neurons that appear at around E10. Embryonic neurogenesis peaks at E13 and ends at ~E17 [2]. During that period, the thickness of the cortical wall increases from ~ 40 (at E11) to ~ 400 μm (at E17) [3], a tenfold enlarge- ment that reflects an intense mitotic activity. In the brain, the vital element zinc (Zn) is involved in a wide array of pathophysiological processes. It is for instance required for a proper brain development and formation, and many neurologic and psychiatric disorders are associated with dysregulated Zn levels. A key feature of Zn in the brain is its accumulation into synaptic vesicles of some neuronal popula- tions [4, 5]. Thus, neuronal firing is associated with the extra- cellular release of this metal which is known to influence the activity of many channels and transporters [6–8]. Zn is now regarded as an endogenous and physiological modulator of synaptic transmission [8, 9]. In addition to its participation in the control of neuronal communication, Zn is reported to be an intracellular messenger controlling a wide diversity of signaling pathways. Intracellular Zn signaling can reflect its uptake and/or its release from internal stores. In neural cells Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-019-1581-7) contains supplementary material, which is available to authorized users. * Alexandre Bouron alexandre.bouron@cea.fr 1 Université Grenoble Alpes, CNRS, CEA, BIG-LCBM, 38000 Grenoble, France 2 ESRF, Grenoble, France 3 Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Université Paris, 75005 Paris, France 4 Laboratoire de Chimie et Biologie des Métaux, UMR CNRS 5249, CEA, 17 rue des Martyrs, 38054 Grenoble, France Molecular Neurobiology https://doi.org/10.1007/s12035-019-1581-7