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MIM – can dilated intracellular spaces lead to cancer?

Source: GMC


Missing-in-metastasis (MIM/MTSS1) is a tissue-specific regulator of actin and plasma membrane dynamics, whose altered expression levels have been linked to metastatic behavior of various cancers. To elucidate the physiological role of the protein Pieta K. Mattila, Juha Saarikangas and collegues generated MIM-deficient mice. The analysis revealed that MIM is dispensable for embryonic development. Heterozygous MIM (MIM+/-) mice were phenotypically normal and fertile and the MIM-deficient mice survived into adulthood and had normal appearance and bodyweight. Surprisingly it turned out that MIM does not modulate Shh signaling in animals or in cultured cells as was proposed before. Morphological analysis as well as Hedgehog-pathway specific signaling assays and further investigations showed that MIM has neither in vivo nor in vitro a role in Shh-signaling.

Urinary concentration defects in MIM null mice

In adult mice, MIM is strongly expressed in the kidney cortex. The testing of 24-hour urine samples from 8 month-old wild-type and MIM-/- littermates within the metabolic screen in the German Mouse Clinic revealed alterations in several parameters. First, MIM null mice displayed significantly higher water intake and urine production compared to wild-type littermates. In addition, urinary wasting of electrolytes (Ca2+, Mg2+, K+, Na+) per 24 hours was increased. These results suggest that MIM-/- mice suffer from reduced tubular water and electrolyte absorption of the kidney. Detailed histological analysis revealed dramatic changes in the kidney morphology. Based on the observed pathological changes, the progression of the kidney disease in MIM-/- mice was categorized into three stages leading to massive fibrosis together with glomerular degeneration in the last stage of the disease. The analysis of kidney ultrastructures using transmission electron microscopy (TEM) revealed atrophic changes of the renal proximal tubules of the mutant mice. The electron microscopy revealed a thickening of the basement membrane and dilated lateral intercellular spaces at the cell-cell contacts(tight junctions), too . The lateral intercellular space represents a pathway for fluid and ion transport and the observed changes in the ultrastructure of MIM-/- kidneys are thus consistent with polyuria and renal electrolyte wasting in these mice.
Similar ultrastructural changes in the kidney epithelia leading to polyuria and electrolyte wasting as described here for MIM-/- mice were previously detected in mice lacking tight junction component claudin 16 as well as in humans suffering from nephronophthisis (NPHP) and kaliopenic nephropathy. This suggests that defects in cell-cell contacts compromising epithelial integrity can reduce osmotic gradient for effective water reabsorption, and thus lead to polyuria.

Reduced bone mass due to disturbed urinary concentration
In the clinical chemistry screen of the GMC, increased plasma alkaline phosphatase (ALP) levels were detected in MIM null mice, suggesting that they have a higher bone turnover rate compared to wild-type mice. Bone densitometry using dual-energy X-ray absorptiometry (DEXA) in the dysmorphology screen confirmed that both bone mineral content (BMC) and bone content were significantly decreased in MIM mutants. This effect might represent a secondary effect of the kidney defect (e.g. altered calcium homeostasis) because MIM expression is undetectable in developing and adult bones and similar bone abnormalities were previously reported for other mutant animals and human diseases with kidney defects.
In the future, it will be important to determine the exact mechanism by which MIM promotes actin and plasma membrane dynamics to maintain cell-cell contacts in various epithelia, and to elucidate how this activity is linked to metastatic behavior of cancers.


Missing-in-metastasis is required for kidney epithelia integrity but is dispensable for Sonic hedgehog signaling, Mattila et al., J Cell Sci. 2011 Apr 15;124(Pt 8):1245-55. Epub 2011 Mar 15.