Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and aging

Abstract

Many premature aging diseases are caused by mutations in the lamin A gene, resulting in severe nuclear abnormalities, but, curiously, although some tissues show severe phenotypes, others are hardly affected. Two new studies, Scaffi di and Misteli (2008) and Espada et al. (see p. 27 of this issue), show that somatic stem cells are misregulated in premature aging, explaining some of the pathological defects observed in these situations. Structure and function of nuclear laminsThe nuclear lamina underlies the inner membrane of the nuclear envelope (inner nuclear membrane [INM]). It is composed of lamins and lamin-associated proteins, including integral proteins of the INM. Lamins interact directly or indirectly with many known INM proteins, several nucleoplasm proteins, and proteins that bridge the inner and outer nuclear membranes and interact with cytoskeleton elements. These lamin-based complexes are involved in most nuclear activities, including determining nuclear structure, spacing of nuclear pores, replication of DNA, regulation of gene expression, transcription by RNA Pol II, nuclear positioning, segregation of chromosomes, meiosis, and apoptosis ( Gruenbaum et al., 2005 ).Lamins are type V intermediate fi lament proteins. They are found in all metazoans, and, like all intermediate fi lament proteins, they are composed of a short globular N-terminal (head) domain, an ␣ -helical rod domain, and a globular C (tail) domain. The tail domain of lamins contains an Ig fold fl anked by unstructured regions. Lamins form stable, fi brous structures both at the nuclear periphery and in the nucleoplasm ( Moir et al., 2000 ;Wiesel et al., 2008 ).Lamins are divided into A and B types based on their expression patterns and protein structure. A-type lamins are found only in more complex metazoans and are expressed in differentiSpecifi c mutations in the human gene encoding lamin A or in the lamin A -processing enzyme, Zmpste24, cause premature aging. New data on mice and humans suggest that these mutations affect adult stem cells by interfering with the Notch and Wnt signaling pathways.

Lamins at a glance

“…This idea is supported by findings of epidermal stem cell depletion in an HGPS mouse model (Rosengardten et al, 2011) and reports of altered Notch and Wnt signaling in human and mouse MSCs expressing progerin, and mouse models of HGPS (Espada et al, 2008;Hernandez et al, 2010;Meshorer and Gruenbaum, 2008;Scaffidi and Misteli, 2008). Thus, increased turnover and abnormal differentiation of adult stem cells, coupled with possibly increased mechanical sensitivity, could result in MSC death and inefficient repair of damaged tissue in HGPS and other laminopathies (reviewed by Halaschek-Wiener and Brooks-Wilson, 2007;Meshorer and Gruenbaum, 2008;Prokocimer et al, 2009). …”

Reduced Lymphocyte Longevity and Homeostatic Proliferation in Lamin B Receptor-Deficient Mice Results in Profound and Progressive Lymphopenia

“…The lamina is made up of filamentous proteins called lamins and several lamin-interacting inner nuclear membrane proteins, including the lamin B receptor (LBR). Although the structural role of the lamina in regulating many nuclear functions, including mitosis and meiosis, has long been recognized, there is increasing evidence that the tethering of heterochromatin to the nuclear periphery and interaction of the nuclear lamina with epigenetic modifiers and transcription factors is important for transcriptional repression (1)(2)(3)(4)(5). Key studies in Drosophila and humans have demonstrated low gene expression is correlated with lamina-associated domains (6,7).…”

The search for evolutionary developmental origins of aging in zebrafish: A novel intersection of developmental and senescence biology in the zebrafish model system

“…On the other hand, the crucial involvement of lamin A and lamina-associated polypeptide 2a in the regulation of stem cells has been suggested previously (Constantinescu et al, 2006;Halaschek-Wiener and Brooks-Wilson, 2007;Espada et al, 2008;Meshorer and Gruenbaum, 2008;Naetar et al, 2008;Scaffidi and Misteli, 2008;Gotic et al, 2010). Because embryonic stem cells appear to express lamin A/C upon differentiation (Constantinescu et al, 2006), and lamin A-associated stem cell dysfunction has been linked to disruption of the Wnt and Notch signaling pathways (Espada et al, 2008;Meshorer and Gruenbaum, 2008;Scaffidi and Misteli, 2008;Hernandez et al, 2010), which are essential for early vertebrate development, our observations of embryonic senescence or apoptosis in LMNA-disturbed zebrafish might be consistent with a dysregulation of somatic stem cells leading to organismal premature aging.…”