Multiple Origins of Secretagogin Expressing Cortical GABAergic Neuron Precursors in the Early Human Fetal Telencephalon.

Ayman Alzu’Bi,Gavin J Clowry

doi:10.3389/fnana.2020.00061

Abstract

Secretagogin (SCGN) which acts as a calcium signaling sensor, has previously been shown to be expressed by a substantial population of cortical GABAergic neurons at mid-gestation in humans but not in mice. The present study traced SCGN expression in cortical GABAergic neurons in human fetal forebrain from earlier stages than previously studied. Multiple potential origins of SCGN-expressing neurons were identified in the caudal ganglionic eminence (CGE) lateral ganglionic eminence (LGE) septum and preoptic area; these cells largely co-expressed SP8 but not the medial ganglionic eminence marker LHX6. They followed various migration routes to reach their target regions in the neocortex, insular and olfactory cortex (OC) and olfactory bulbs. A robust increase in the number of SCGN-expressing GABAergic cortical neurons was observed in the midgestational period; 58% of DLX2+ neurons expressed SCGN in the cortical wall at 19 post-conceptional weeks (PCW), a higher proportion than expressed calretinin, a marker for GABAergic neurons of LGE/CGE origin. Furthermore, although most SCGN+ neurons co-expressed calretinin in the cortical plate (CP) and deeper layers, in the marginal zone (MZ) SCGN+ and calretinin+ cells formed separate populations. In the adult mouse, it has previously been shown that in the rostral migratory stream (RMS), SCGN, annexin V (ANXA5), and matrix metalloprotease 2 (MMP2) are co-expressed forming a functioning complex that exocytoses MMP2 in response to calcium. In the present study, ANXA5 showed widespread expression throughout the cortical wall, although MMP2 expression was very largely limited to the CP. We found co-expression of these proteins in some SCGN+ neurons in the subventricular zones (SVZ) suggesting a limited role for these cells in remodeling the extracellular matrix, perhaps during cell migration.

Highlights

Secretagogin is an EF-hand calcium-binding protein similar in sequence and structure to calbindin (CalB) and calretinin (CalR) these proteins are likely to have different functions (Schwaller, 2009)
A ground-breaking study (Raju et al, 2018) demonstrated that expression of SCGN by cortical GABAergic neurons during development originating from the caudal and lateral ganglionic eminence (CGE and LGEs) at mid-gestation is a feature of human but not the mouse
Intense SCGN expression was mainly restricted to the ventral telencephalon including the post-mitotic zones of the LGE, medial ganglionic eminence (MGE), and anterior entopeduncular nucleus/preoptic area (AEP/POA) with no expression seen in the dorsal telencephalon (Figure 1A)

Summary

Introduction

Secretagogin is an EF-hand calcium-binding protein similar in sequence and structure to calbindin (CalB) and calretinin (CalR) these proteins are likely to have different functions (Schwaller, 2009). SCGN is known to have an important role in exocytosis in certain cells, for instance, pancreatic beta cells and neuroendocrine cells of the hypothalamus (Wagner et al, 2000; Romanov et al, 2015; Yang et al, 2016). SCGN is co-expressed by a subset of GABAergic parvocellular neurons but not exclusively by this subset (Romanov et al, 2015). A much higher density of both cell body and neuropil staining is observed in the human hippocampal and parahippocampal formations (Attems et al, 2007; TapiaGonzález et al, 2020)

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