Local regulation of fat metabolism in peripheral nerves

Abstract

We comprehensively analyzed gene expression during peripheral nerve development by performing microarray analyses of premyelinating, myelinating, and postmyelinating mouse sciatic nerves, and we generated a database of candidate genes to be tested in mapped peripheral neuropathies. Unexpectedly, we identified a large cluster of genes that are (1) maximally expressed only in the mature nerve, after myelination is complete, and (2) tied to the metabolism of storage (energy) lipids. Many of these late-onset genes are expressed by adipocytes, which we find constitute the bulk of the epineurial compartment of the adult nerve. However, several such genes, including SREBP-1, SREBP-2, and Lpin1, are also expressed in the endoneurium. We find that Lpin1 null mutations lead to lipoatrophy of the epineurium, and to the dysregulation of a battery of genes required for the regulation of storage lipid metabolism in both the endoneurium and peri/epineurium. Together with the observation that these mutations also result in peripheral neuropathy, our findings demonstrate a crucial role for local storage lipid metabolism in mature peripheral nerve function, and have important implications for the understanding and treatment of peripheral neuropathies that are commonly associated with metabolic diseases such as lipodystrophy and diabetes. Among the most complex cellular interactions in vertebrate neural development is the interplay of neurons, glia, and mesenchymal cells that leads to the formation of peripheral nerves. A subset of these interactions occurs between neurons and Schwann cells, and results in the elaboration of myelin. This Schwann cell organelle consists of an extended sheet of specialized glial membrane that is repeatedly wrapped and then tightly compacted around axons (Webster 1971;Low 1976;Garbay et al. 2000). It provides the insulation upon which the rapid, saltatory conduction of neuronal action potentials is entirely dependent, and the loss of myelin integrity in demyelinating diseases is invariably debilitating (Keegan and Noseworthy 2002).Peripheral nerves are composed of three distinct tissue compartments: the epineurium, perineurium, and endoneurium. The outermost epineurium surrounds a thin lamellated perineurium, which in turn surrounds the fascicle of axons, Schwann cells, and fibroblasts that make up the endoneurium. Schwann cells, the most abundant cells of the endoneurium, are derived from the neural crest via a multistep differentiation process involving the formation of a Schwann cell precursor that is present in mouse nerves beginning at embryonic day 12 to 13 (E12-E13), and subsequently, of an immature Schwann cell, present from E15 to birth (Jessen and Mirsky 1999). During the first postnatal week, a subset of immature Schwann cells exit the cell cycle, lose susceptibility to apoptosis, synthesize a basement membrane, and begin to myelinate their associated axons . Myelination of peripheral nerves peaks in the second postnatal week in the mouse, after which the process substantially slows; only ...

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…49 To our knowledge, there is no specific studies so far about the impact of the SREBP pathway in myelination in the central nervous system, but several studies have demonstrated the importance of this pathway in the peripheral myelination of axons. 50,51 The present implication of SREBF1 and SREBF2 as genetic susceptibility factors in schizophrenia further underscores the importance of lipid biosynthesis and myelination in the pathophysiology of schizophrenia.…”

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…In the case of myelinating cells this involves downregulation of a large number of genes related to myelination (reviewed in Jessen and Mirsky, 2005;Mirsky et al, 2008;Scherer and Salzer, 2001). This includes enzymes that provide for cholesterol synthesis, structural proteins such as P 0 , myelin basic protein (MBP), and membrane associated proteins such as myelin associated glycoprotein (MAG) and periaxin (Buchstaller et al, 2004;D'Antonio et al, 2006;Leblanc et al, 2005;Nagarajan et al, 2001Nagarajan et al, , 2002Verheijen et al, 2003). This switch-off is accompanied by the activation of another group of molecules, most of which are normally found on immature cells prior to myelination.…”

Neuregulin‐1, a key axonal signal that drives Schwann cell growth and differentiation

“…Myelination requires the activation and high-level expression of myelin-specific genes, and the production of vast quantities of myelin membrane (Nagarajan et al, 2002;Verheijen et al, 2003). The process of myelination results in a huge increase in the size of a Schwann cell, particular of its membrane surface area, which was estimated to increase within a few days up to several thousand fold.…”