LA Larsen Group
We are interested in understanding the fundamental aspects of human embryonic development and birth defects. Our main research focus is genetic and functional aspects of human cardiac development and congenital heart disease. However, many developmental genes and molecular mechanisms are not functionally restricted to a single organ, thus we are also interested in investigating genetic and molecular mechanisms involved in other areas of human embryonic development, including development of the brain.
Congenital heart disease
Congenital heart disease (CHD) is gross structural abnormalities of the heart and intrathoratic vessels. This is the most common group of inborn malformations, with an incidence of almost 1% in the population. The etiology of CHD is complex but with a significant genetic component. Large families with CHD are very rare and CHD is a very heterogeneous disorder, thus it is difficult to identify the causative variants in CHD patients and the genetics and pathophysiology of CHD is generally not well understood.
Identification of genes and pathophysiological mechanisms associated with cardiac development and CHD is likely to have an impact on early diagnosis and prevention of CHD and may also provide a basis for development of new drug therapies e.g. for minor cardiac defects like small atrial- and ventricular defects. Furthermore, identifying and understanding molecular mechanisms in human cardiac development, especially the subset of genes and molecular networks which regulate cardiomyogenesis is likely to have an impact on the development of therapeutic means for regeneration of cardiomyocytes in myocardial infarction and congestive heart failure.
Heart development is a complex process, which involves establishment of a primitive heart tube, looping of the heart tube, followed by chamber formation, chamber septation and development of the cardiac valves and outflow tract (figure 1).
Figure 1. Developmental stages of the heart (Koefoed et al., 2014).
Development of the heart is coordinated by a significant number of cellular signaling networks like the Hedgehog, WNT, TGF-beta signaling pathways. Furthermore, most of the known human CHD disease genes are involved in different aspects of cellular signaling (figure 2). Thus, we are also interested in exploring the mechanisms and organelles which regulate signaling transduction during heart development and cardiomyogenesis, for example the primary cilium.
Figure 2. Schematic representation of the different cell signaling components affected by mutations in human CHD disease genes ( Andersen et al., 2014 ).
Current Project Areas
We explore different genomic strategies for identification of genes, genomic regulatory regions and molecular networks involved in cardiac development and disease. To this end we are currently investigating families where CHD is found in several family members. We investigate the function of the candidate genes or signaling pathways by expression analysis in embryonic tissues and functional assays in cell models and zebrafish.
In collaboration with the Disease Systems Biology group at NNF Center for Protein Research, UCPH we are using systems biology approaches to investigate cardiac developmental mechanisms and interpret genetic variants identified in CHD patients.
In collaboration with the Cilia Group at Department of Biology, UCPH we are investigating how the primary cilium is coordinating signaling pathways during embryonic development.
Mönnich M, Borgeskov L, Breslin L, Jakobsen L, Rogowski M, Doganli C, Schrøder JM, Mogensen JB, Blinkenkjær L, Harder LM, Lundberg E, Geimer S, Christensen ST, Andersen JS, Larsen LA, Pedersen LB (2018) CEP128 localizes to the subdistal appendages of the mother centriole and regulates TGF-β/BMP signaling at the primary cilium. Cell reports 22:2584-2592.
Ellesøe SG, Workman CT, Bouvagnet P, Loffredo CA, McBride KL, Hinton RB, van Engelen K, Gertsen EC, Mulder BJM, Postma AV, Anderson RH, Hjortdal VE, Brunak S, Larsen LA (2018) Familial co-occurrence of congenital heart defects follows distinct patterns. Eur Heart J 39:1015-22.
Schmid F, Schou KB, Vilhelm MJ, Holm MS, Breslin L, Farinelli P, Larsen LA, Andersen JS, Pedersen LB, Christensen ST (2018) IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases. J Cell Biology 217:151-161.
Andersen TA, Troelsen KDL, Larsen LA (2014) Of Mice and Men: Molecular Genetics of Congenital Heart Disease. Cell Mol Life Sci 71:1327-52
Clement CA, Ajbro KD, Koefoed K, Vestergaard ML, Veland IR, Henriques de Jesus MP, Pedersen LB, Benmerah A, Andersen CY, Larsen LA, Christensen ST (2013) TGF-β Signaling Is Associated with Endocytosis at the Pocket Region of the Primary Cilium. Cell Reports 3:1806-14.
Lage K, Greenway S, Rosenfeld JA, Wakimoto H, Gorham JM, Segre A, Roberts AE, Smoot LB, Pu WT, Pereira AC, Mesquita SM, Tommerup N, Brunak S, Ballif BC, Schaffer L, Donahoe PK, Daly MJ, Seidman JG, Seidman CE and Larsen LA (2012) Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci U S A 109:14035-40.
Thienpont B, Zhang L, Postma AV, Breckpot J, Tranchevent L-C, Van Loo P, Møllgård K, Tommerup N, Bache I, Tümer Z, van Engelen K, Menten B, Mortier G, Waggoner D, Gewillig M, Moreau Y, Devriendt K and Larsen LA (2010) Haplo-insufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet 86:1-11.
Lage K, Møllgård K, Greenway S, Wakimoto H, Gorham JM, Workman CT, Bendsen E, Hansen NT, Rigina O, Roque FS, Wiese C, Christoffels VM, Roberts AE, Smoot LB, Pu WT, Donahoe PK, Tommerup N, Brunak S, Seidman CE, Seidman JG and Larsen LA (2010) Dissecting spatio-temporal protein networks driving human heart development and related disorders. Mol Syst Biol 6:381.
Clement CA, Kristensen SG, Møllgård K, Yoder B, Pazour GJ, Larsen LA and Christensen ST (2009) The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation. J Cell Sci 122:3070-3082.
Erdogan F, Larsen LA, Zhang L, Tümer Z, Tommerup N, Chen W, Jacobsen JR, Schubert M, Jurkatis J, Tzschach A, Ropers H-H and llmann R. (2008) High frequency of submicroscopic genomic aberrations detected by tiling path array CGH in patients with isolated congenital heart disease. J Med Genet 45:704-70