Secretagogin is a Ca ²⁺ -binding protein specifying subpopulations of telencephalic neurons

Abstract

The Ca 2؉ -binding proteins (CBPs) parvalbumin, calbindin, and calretinin are phenotypic markers of terminally differentiated neurons in the adult brain. Although subtle phylogenetic variations in the neuronal distribution of these CBPs may occur, morphologically and functionally diverse subclasses of interneurons harbor these proteins in olfactory and corticolimbic areas. Secretagogin (scgn) is a recently cloned CBP from pancreatic ␤ and neuroendocrine cells. We hypothesized that scgn is expressed in the mammalian brain. We find that scgn is a marker of neuroblasts commuting in the rostral migratory stream. Terminally differentiated neurons in the olfactory bulb retain scgn expression, with scgn being present in periglomerular cells and granular layer interneurons. In the corticolimbic system, scgn identifies granule cells distributed along the dentate gyrus, indusium griseum, and anterior hippocampal continuation emphasizing the shared developmental origins, and cytoarchitectural and functional similarities of these neurons. We also uncover unexpected phylogenetic differences in scgn expression, since this CBP is restricted to primate cholinergic basal forebrain neurons. Overall, we characterize scgn as a neuronspecific CBP whose distribution identifies neuronal subtypes and hierarchical organizing principles in the mammalian brain.cortex ͉ development ͉ interneuron ͉ neurogenesis ͉ stem cell T he ability to release neurotransmitters at chemical synapses, to integrate the activity of diverse synaptic inputs and trigger molecular mechanisms underlying neuronal adaptation, as well as to maintain excitability in neurons rely on the refined spatial and temporal control of momentary changes in cytosolic [Ca 2ϩ ] (1, 2). Ca 2ϩ -binding proteins (CBPs) represent a means to effectively regulate intracellular Ca 2ϩ dynamics (3). Members of the EF-hand family of CBPs invariably contain a 3-D motif to bind Ca 2ϩ at its physiological cytosolic concentrations (4). Some ancestral representatives of this protein family, such as calmodulin, are ubiquitously expressed with a high degree of evolutionary conservation and are involved in the control of fundamental cellular functions ranging from the cell cycle, cell motility and axon polarization to synaptic signaling (3). In contrast, the parvalbumin (PV) and calbindin subfamilies of CBPs, the latter including the vitamin D-dependent 28 kDa isoform of calbindin (CB) and calretinin (CR), exhibit restricted tissue-specific expression patterns in vertebrates (5, 6). During the past decades, PV, CB, and CR received significant attention because of their exquisite developmentally regulated cell type-specific expression in the mammalian nervous system (6-8).CBPs show a unique association with newly generated neurons in the adult brain (9, 10). Neural progenitors that are born in the subependymal zone and migrate in the rostral migratory stream (RMS) to differentiate into interneurons in the olfactory bulb (OB) commonly express CR at their neuroblast stage with select subpopulations ...

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

“…Finally, we tested whether mPFC‐targeting NE neurons respond to CNTF by injecting AAVs encoding the Ca 2+ indicator GCaMP6 in a Cre‐dependent manner into the PFC (Fig 3G). For this, we have developed secretagogin ( Scgn )‐Cre mice (Appendix Fig S2D and D1) because secretagogin, an EF‐hand tetra‐Ca 2+ ‐sensor protein (Wagner et al , 2000; Alpár et al , 2012; Romanov et al , 2015), is abundantly expressed in NE neurons residing in LC (Mulder et al , 2009). Fourteen days after viral GCaMP6 delivery, we used Ca 2+ imaging to monitor whether CNTF superfusion affects NE neurons ex vivo .…”

“…As such, NE neurons in both rodents (Figs 4B–B2 and EV2A–D) and humans (Fig 5A and A1) meet these criteria since they express secretagogin (Figs 4B1 and 5A1). Secretagogin is neuron‐specific in mammalian brain (Mulder et al , 2009) and also coordinates acute stress‐induced fast CRH release from parvocellular neurons at the median eminence (Romanov et al , 2015). Besides somatic expression (Fig EV2C), we localized secretagogin to both NE dendrites (Fig EV2C1) and axons (Figs EV2D and EV4B), including synaptosomes (Fig EV2F), suggesting that its interactome could modulate NE activity even at locations positioned distally from NE perikarya.…”

“…Animals were routinely perfusion‐fixed with 4% PFA in 0.1M PB (pH 7.4) under deep anesthesia as described (Alpár et al , 2014; Lendvai et al , 2013; Mulder et al , 2009; Romanov et al , 2015). …”

Secretagogin is Expressed by Developing Neocortical GABAergic Neurons in Humans but not Mice and Increases Neurite Arbor Size and Complexity

“…Scgn expression has been reported in a variety of neuronal subtypes in mammalian brains (Mulder et al 2009(Mulder et al , 2010) (further reviewed in Alpar et al 2012), but its cellular origins in prenatal human brain have not been described. Immunofluorescent staining revealed SCGN expression in a large number of cells from the ventricular zone to the pial surface of GW18 human neocortex ( Fig.…”

Expression of the calcium binding proteins Necab-1,-2 and -3 in the adult mouse hippocampus and dentate gyrus

“…Secretagogin (Mulder et al, 2009) is a recent addition to the field of these useful tags of neuronal subpopulations.…”