Molecular Cell Biology

Nuclear Lamins in Health and Disease

Aim

Nuclear lamins are key proteins in the mechanical functioning of cells. Especially, proteins from the LMNA gen (lamin A, lamin C and lamin Adel10) appear to determine cellular stiffness and mechanoresponse. Laminopathies arise in patients with LMNA mutations, with a disease phenotype ranging from Hutchison Gilford progeria to muscle and fat tissue–related disorders, such as dilated cardiomyopathy and partial lipodystrophy. In all, LMNA mutations lead to about 20 different clinical diseases, depending on the localisation of the mutation and as yet unknown additional factors in disease development.
In our group we study the cellular effects of LMNA mutations, using vital microscopy, advanced high-resolution microscopy (STED), as well as standard molecular techniques.

The impact of alterations in LMNA expression on mechanical properties of these cells is studied in close cooperation with Dr. Carlijn Bouten (Eindhoven University of Technology, Dept. of Biomedical engineering).

Detailed microscopic analyses of dermal fibroblast from patients with LMNA mutations will lead to functional assays to predict disease development. These studies are performed in close cooperation with dr. Arthur van den Wijngaard (Maastricht University, Dept. of Clinical genetics, Cardiogenetics).

The downregulation of A-type lamins leads to increased mobility of tumor cells, allowing improved capabilities of tumor invasion and metastasis. Together with Dr. Jürgen Becker (Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Germany) we investigate the impact of LMNA downregulation on the behaviour of Merkel cell carcinomas....

Key publications

  1. Tamiello C, Buskermolen AB, Baaijens FP, Broers JLV, Bouten CV. Heading in the right direction: understanding cellular orientation responses to complex biophysical environments. Cell Mol Bioeng 9:12-37, 2016.
  2. Broers JL, Ramaekers FC. The role of the nuclear lamina in cancer and apoptosis. Adv Exp Med Biol 773:27-48, 2014.
  3. Tamiello C, Kamps MA, van den Wijngaard A, Verstraeten VL, Baaijens FP, Broers JL, Bouten CC. Soft substrates normalize nuclear morphology and prevent nuclear rupture in fibroblasts from a laminopathy patient with compound heterozygous LMNA mutations. Nucleus 4:61-73, 2013.
  4. De Vos WH, Houben F, Kamps M, Malhas A, Verheyen F, Cox J, Manders EM, Verstraeten VL, van Steensel MA, Marcelis CL, van den Wijngaard A, Vaux DJ, Ramaekers FC, Broers JL. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet 20:4175-4186, 2011.
  5. Verstraeten VL, Broers JL, van Steensel MA, Zinn-Justin S, Ramaekers FC, Steijlen PM, Kamps M, Kuijpers HJ, Merckx D, Smeets HJ, Hennekam RC, Marcelis CL, van den Wijngaard A. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation. Hum Mol Genet. 15:2509-2522, 2006.
  6. Broers JL, Ramaekers FC, Bonne G, Yaou RB, Hutchison CJ. Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev 86:967-1008, 2006.
  7. Broers JL, Peeters EA, Kuijpers HJ, Endert J, Bouten CV, Oomens CW, Baaijens FP, Ramaekers FC. Decreased mechanical stiffness in LMNA-/- cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies. Hum Mol Genet 13:2567-2580, 2004.
  8. Broers JL, Machiels BM, van Eys GJ, Kuijpers HJ, Manders EM, van Driel R, Ramaekers FC. Dynamics of the nuclear lamina as monitored by GFP-tagged A-type lamins. J Cell Sci. 112:3463-3475, 1999.

Team leader

Jos Broers, PhD
T: (+31) (0)43 3881366
E: jos.broers@maastrichtuniversity.nl

Research group

Technician: Miriam Kamps

School

CARIM