Neuroanatomical characterisation of the expression of the lipodystrophy and motor-neuropathy gene Bscl2 in adult mouse brain.

Alastair S Garfield,Lora K Heisler,Rowena J Dennis,Wai S Chan,Daisuke Ito,Justin J Rochford

doi:10.1371/journal.pone.0045790

Abstract

The endoplasmic reticulum localised protein seipin, encoded by the gene Berardinelli–Seip congenital lipodystrophy type 2 (BSCL2), serves a critical but poorly defined function in the physiology of both adipose and neural tissue. In humans, BSCL2 loss-of-function mutations cause a severe form of lipodystrophy, whilst a distinct set of gain-of-toxic-function mutations are associated with a heterogeneous group of neuropathies. However, despite the importance of seipin dysfunction to the pathophysiology of these conditions, little is known about its physiological role in adipocytes or neurons. BSCL2 mRNA has previously been identified in human and mouse brain, yet no definitive assessment of its expression has been undertaken. Here we comprehensively characterised the neuroanatomical distribution of mouse Bscl2 using complementary in situ hybridisation histochemistry and immunohistochemistry techniques. Whilst Bscl2 was broadly expressed throughout the rostral-caudal extent of the mouse brain, it exhibited a discrete neuroanatomical profile. Bscl2 was most abundantly expressed in the hypothalamus and in particular regions associated with the regulation of energy balance including, the paraventricular, ventromedial, arcuate and dorsomedial nuclei. Bscl2 expression was also identified within the brainstem dorsal vagal complex, which together with the paraventricular nucleus of the hypothalamus represented the site of highest expression. Further neurochemical profiling of these two nuclei revealed Bscl2/seipin expression within energy balance related neuronal populations. Specifically, seipin was detected in oxytocin neurons of the paraventricular nucleus of the hypothalamus and in catecholamine neurons of the dorsal vagal complex. These data raise the possibility that in addition to its role in adipose tissue development, seipin may also be involved in the central regulation of energy balance.

Highlights

The resident endoplasmic reticulum protein, seipin, encoded by the Berardinelli–Seip congenital lipodystrophy type 2 (BSCL2) gene, has been implicated in both metabolic and neurological disease
Expression was significantly lower; only scattered cells were evident within the globus pallidus and no detectable expression was observed within the caudate putamen (Fig. 2C)
Bscl2 mRNA expression was highest in medial septal nucleus (MS; Fig. 2C, D) and extended ventrolaterally into the nucleus of the diagonal band and magnocellular preoptic area (MCPO; Fig. 2D)

Summary

Introduction

The resident endoplasmic reticulum protein, seipin, encoded by the BSCL2 gene, has been implicated in both metabolic and neurological disease. BSCL2 was originally identified in a genetic screen of patients suffering from a severe syndrome of congenital generalised lipodystrophy (Berardinelli–Seip congenital lipodystrophy type 2) with autosomal recessive inheritance [5] In these cases a range of point, premature stop, deletion or frameshift mutations in BSCL2 are likely to cause a loss of seipin function and lead to an almost complete absence of adipose tissue [5,6,7,8]. BSCL2 point mutations that affect an N-glycosylation site at amino acid 88 (N88S or S90L) result in aggregation of the mutant seipin protein and the proposed pathogenic activation of ER stress pathways [3,13,14] These seipinopathies exhibit broad phenotypic variance across patients but are defined by upper, lower and/or peripheral motor neuron disturbance but no apparent metabolic symptoms. Murine modelling of BSCL2 pathologies reveals significant functional conservation between humans and mice, such that whilst Bscl ablation leads to lipodystrophy [15] the overexpression of an N88S mutant transgene promotes progressive motor deficits [16]

Methods

Results

Conclusion