Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells

Abstract

Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot–Marie–Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4–Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4–Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.

DDIT4/REDD1/RTP801 Is a Novel Negative Regulator of Schwann Cell Myelination

“…This latter observation led to the hypothesis that myelin outfoldings represent a PIP 3 -dependent phenomenon, whereas tomacula are linked to the bulk of protein and lipid synthesis that is dependent on mTORC1 activation. This hypothesis is further supported by the fact that loss of either the MTMR2 phospholipid phosphatase (Bolino et al, 2000(Bolino et al, , 2004 or the guanosine nucleotide exchange factor for cdc42, FGD4 (Stendel et al, 2007;Horn et al, 2012), which binds to phospholipids, provokes demyelinating neuropathies with myelin outfoldings.…”

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

“…CMT4H is an early-onset peripheral neuropathy caused by mutations in the Fdg4 gene that encodes FGD1-related actin filament-binding protein (Frabin), a guanine nucleotide exchange factor for the Rho GTPase Cdc42 [72]. Frabin is expressed in a wide variety of tissues, and its cellular function remains poorly understood.…”

“…Frabin is expressed in a wide variety of tissues, and its cellular function remains poorly understood. A recent study has shown that shRNA-mediated depletion of endogenous Frabin leads to inhibition of transferrin receptor internalization in rat RT4 Schwann cells [72], suggesting a role of Frabin in regulation of endocytosis. Because CMT4H is a recessively inherited disease caused by loss-of-function mutations in Frabin, these results implicate endocytosis impairment as a potential pathogenic mechanism in CMT4H neuropathy.…”

Late Onset Neuropathy with Spontaneous Clinical Remission in Mice Lacking the POZ Domain of the Transcription Factor Myc-interacting Zinc Finger Protein 1 (Miz1) in Schwann Cells

“…Myelin outfoldings similar to the pathology observed in Miz1⌬POZ mice are characteristic histopathological features in a limited number of inherited peripheral neuropathies (45)(46)(47)(48)(49)(50). The underlying pathomechanism has been attributed to dysregulated phosphoinositide levels and impaired vesicular transport (45, 46, 48, 50 -52).…”