Peripheral Myelin Protein 22 Is in Complex with α6β4 Integrin, and Its Absence Alters the Schwann Cell Basal Lamina

Abstract

Peripheral myelin protein 22 (PMP22) is a tetraspan membrane glycoprotein, the misexpression of which is associated with hereditary demyelinating neuropathies. Myelinating Schwann cells (SCs) produce the highest levels of PMP22, yet the function of the protein in peripheral nerve biology is unresolved. To investigate the potential roles of PMP22, we engineered a novel knock-out (Ϫ/Ϫ) mouse line by replacing the first two coding exons of pmp22 with the lacZ reporter. PMP22-deficient mice show strong ␤-galactosidase reactivity in peripheral nerves, cartilage, intestines, and lungs, whereas phenotypically they display the characteristics of tomaculous neuropathy. In the absence of PMP22, myelination of peripheral nerves is delayed, and numerous axon-SC profiles show loose basal lamina, suggesting altered interactions of the glial cells with the extracellular matrix. The levels of ␤4 integrin, a molecule involved in the linkage between SCs and the basal lamina, are severely reduced in nerves of PMP22-deficient mice. During early stages of myelination, PMP22 and ␤4 integrin are coexpressed at the cell surface and can be coimmunoprecipitated together with laminin and ␣6 integrin. In agreement, in clone A colonic carcinoma cells, epitope-tagged PMP22 forms a complex with ␤4 integrin. Together, these data indicate that PMP22 is a binding partner in the integrin/laminin complex and is involved in mediating the interaction of SCs with the extracellular environment.

Laminin-5 activates extracellular matrix production and osteogenic gene focusing in human mesenchymal stem cells

“…Table 1 lists representative genes for each area, plus annotation of which other treated populations these genes appear in (the complete list is available at http://www.rpi.edu/∼bennek/TissueEng/ln5.html). Area 1 (Ln-5 hMSC) was characterized by a number of genes encoding signaling proteins, many of which are associated with ECMstimulated pathways, cell survival, and regulation of cell growth in non-osteoblast lineages (e.g., caldesmon [Hai et al, 2006]; calpain 2 [Westhoff et al, 2004]; beta4 associated protein [Amici et al, 2006]). Most of these genes (31 of 46) were found in Area 1 for hMSC stimulated by collagen I, vitronectin, or OS medium as well (e.g., Table 1, column 3).…”

6 4 Integrin and Dystroglycan Cooperate to Stabilize the Myelin Sheath

“…β4 integrin interacts with Pmp22, but mutant mice have different severity of phenotypes β4 integrin has recently been shown to form a complex with Pmp22 (Amici et al, 2006). Heterozygous loss-of-function mutations in PMP22 in mice and men cause a milder tomacular neuropathy, evident only after compression (Hereditary Neuropathy with liability to Pressure Palsy (HNPP).…”

“…Heterozygous loss-of-function mutations in PMP22 in mice and men cause a milder tomacular neuropathy, evident only after compression (Hereditary Neuropathy with liability to Pressure Palsy (HNPP). Heterozygous null mice for Pmp22 resemble HNPP pathology (Adlkofer et al, 1995), whereas homozygous null mice have a severe dys-and de-myelinating neuropathy with both hypomyelination and tomacula (Adlkofer et al, 1995;Amici et al, 2006). In these mice, an impaired organization of the basal lamina and a drastic reduction in the levels of β4 integrin was reported, suggesting a role for Pmp22 in stabilizing laminin-integrin interactions (Amici et al, 2006).…”

“…Heterozygous null mice for Pmp22 resemble HNPP pathology (Adlkofer et al, 1995), whereas homozygous null mice have a severe dys-and de-myelinating neuropathy with both hypomyelination and tomacula (Adlkofer et al, 1995;Amici et al, 2006). In these mice, an impaired organization of the basal lamina and a drastic reduction in the levels of β4 integrin was reported, suggesting a role for Pmp22 in stabilizing laminin-integrin interactions (Amici et al, 2006). A hypothesis arising from this observation is that laminin-integrin interactions at the basal lamina contribute to the stability of the myelin sheath.…”

“…Fourth, α6β4 integrin in epithelia amplifies neuregulin signaling (Guo et al, 2006), which is crucial at multiple stages of Schwann cell development (reviewed in (Nave and Salzer, 2006). Finally α6β4 integrin interacts with PMP-22, a myelin protein mutated in Charcot-Marie-Tooth 1A neuropathy (Amici et al, 2006). Against a role for α6β4 integrin, myelination starts normally in newborn nerves and dorsal root ganglia explants from mice dying at post-natal day 1 (P1) due to β4 inactivation (Frei et al, 1999).…”