Recent Progress on Genetically Modified Animal Models for Membrane Skeletal Proteins: The 4.1 and MPP Families

Abstract

The protein 4.1 and membrane palmitoylated protein (MPP) families were originally found as components in the erythrocyte membrane skeletal protein complex, which helps maintain the stability of erythrocyte membranes by linking intramembranous proteins and meshwork structures composed of actin and spectrin under the membranes. Recently, it has been recognized that cells and tissues ubiquitously use this membrane skeletal system. Various intramembranous proteins, including adhesion molecules, ion channels, and receptors, have been shown to interact with the 4.1 and MPP families, regulating cellular and tissue dynamics by binding to intracellular signal transduction proteins. In this review, we focus on our previous studies regarding genetically modified animal models, especially on 4.1G, MPP6, and MPP2, to describe their functional roles in the peripheral nervous system, the central nervous system, the testis, and bone formation. As the membrane skeletal proteins are located at sites that receive signals from outside the cell and transduce signals inside the cell, it is necessary to elucidate their molecular interrelationships, which may broaden the understanding of cell and tissue functions.

Keywords: bone formation; membrane palmitoylated protein; membrane skeleton; nervous system; protein 4.1G; testis.

Figure 1

Schematic representation of an erythrocyte membrane skeleton. The spectrin–actin network structure is connected by protein 4.1R-membrane palmitoylated protein 1 (MPP1) and ankyrin to the intramembranous proteins glycophorin C (GPC) and band 3, respectively. The concept was obtained from previous research [4].

Figure 2

Schematic representation of the relationships among membrane skeletal proteins (4.1, MPP, and CADM) in the PNS (a), CNS (b), and testis (c). Note the different interdependences among those proteins in different organs, revealed by the genetic depletion of the proteins. The picture is partially modified from a previous paper [51].

Figure 3

(a): Schematic representation of MPP2-relating proteins in the cerebellar glomerulus. Note that MPP2 interacts with various adhesion molecules, such as CADM1 and M-cadherin, as well as signal transduction proteins such as CASK and Lin7. GAD: glutamic acid decarboxylase, VGLUT1: vesicular glutamate transporter 1. The picture is partially modified from a previous paper [79]. (b–k): Localization of MAGUKs (MPP2 (a,f), DLG2 (b,g), PSD95 (c,h), CASK (d,i), and SAP97 (Dlg1) (e,j)) in the cerebellar cortex in MPP2+/+ (a–e) and MPP-/- (f–j) mice. Note that MPP2 is mainly observed in the granular layer (GL). ML: molecular layer, PCL: Purkinje cell layer.

Figure 4

Comparative localization of GABAARα1 (a,f,k) with MPP2 (b,c), gephyrin (g,h) and GABAARα6 (l,m) in mouse cerebellar glomeruli. Examples of two-color overlapping regions are shown in (d,e,i,j,n,o) from areas in pictures (c,h,m), respectively. Detailed count data regarding the overlap is described in the text. The right lane demonstrates a summarized schematic drawing of their localizations obtained by immunohistochemistry; it does not consider how to make GABA_AR with five subunits.