Keith R. Porter Lecture, 1996. Of mice and men: genetic disorders of the cytoskeleton.

Abstract

Since the time when I was a postdoctoral fellow under the supervision of Dr. Howard Green, then at the Massachusetts Institute of Technology, I have been interested in understanding the molecular mechanisms underlying growth, differentiation, and development in the mammalian ectoderm. The ectoderm gives rise to epidermal keratinocytes and to neurons, which are the only two cell types of the body that devote most of their protein-synthesizing machinery to developing an elaborate cytoskeletal architecture composed of 10-nm intermediate filaments (IFs). Our interest is in understanding the architecture of the cytoskeleton in keratinocytes and in neurons, and in elucidating how perturbations in this architecture can lead to degenerative diseases of the skin and the nervous system. I will concentrate on the intermediate filament network of the skin and its associated genetic disorders, since this has been a long-standing interest of my laboratory at the University of Chicago.

Modulation of Cell Proliferation by Cytokeratins K10 and K16

“…7B). The ⌬C⌬coil mutant protein, in agreement with data from previous studies (5,6,8), provokes the collapse of the endogenous keratin cytoskeleton similarly to mutated keratins found in epithelial fragility diseases (3,5,6,15).…”

Protein phosphatase inhibition in normal and keratin 8/18 assembly-incompetent mouse strains supports a functional role of keratin intermediate filaments in preserving hepatocyte integrity

“…This theory is supported by the epidermolysis bullosa simplex skin disease, which harbors a K14 mutation inducing impairment of keratin filament formation, with consequent signs of cytolysis and/or degeneration in the basal layers of the skin. These degenerated ''vacuole''-like structures 4 resemble the vacuoles we observed in mK8Ϫ/Ϫ and F22 MC-LR-treated mice. In transgenic mice that express K14 in the liver with consequent hepatocyte IF disruption, inflammatory infiltration, ballooning degeneration, increased fat-containing vacuoles, and glycogen accumulation were also observed.…”

“…1,2 There is significant evidence for the structural importance of epidermal keratins, 3 a functional role that is well illustrated by a number of severe skin and corneal diseases associated with keratin mutations. [4][5][6] Keratins participate in attachment to basement membranes as well as in intercellular contacts, by interacting with specific desmosomal and hemidesmosomal proteins. 3 Furthermore, there are indications that they could be linked to microfilaments (MFs) and microtubules (MTs), 3,[7][8][9] and may be of importance for intracellular organization.…”

Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18

“…12 K18 arg89 is a highly conserved site among keratins and a frequently mutated amino acid in several severe human skin diseases. 4 K18C mice with this dominant-negative mutation develop mild chronic hepatitis and markedly fragile hepatocytes in association with K8/18 filament disruption. 12 K18C mouse hepatocytes have disrupted keratin IFs and increased K8/18 phosphorylation and glycosylation.…”

“…1,2 Characteristic for keratins is that they are obligate heteropolymers, so that at least one type I and one type II keratin are needed for filament formation. [2][3][4][5][6] In hepatocytes, the IFs are composed of K8/18 filaments that form a pericanalicular sheet supporting the bile canaliculus 7,8 and a cytoplasmic network of filaments maintaining the integrity of hepatocytes. 5,7,9 In mouse pancreas, there are two distinct pools of keratin IFs: a cytoplasmic network consisting of K8/18 and an apicolateral band-like network consisting of K8/18/19.…”