BSRT Graduate School

Project 6

Organoid disease models for spinal muscular atrophy

Garcia-Perez, Angélica
Supervisor 1: 
Gouti, Mina
Supervisor 2: 
Schülke, Markus

Our bodies are designed to execute movements such as walking, jumping and handling objects instructed by our neuromuscular system. These movements are produced by temporal and spatial patterns of muscular contractions orchestrated by neurons of the brain and spinal cord. Spinal cord MNs connect with skeletal muscles with great specificity in order to form functional neuromuscular junctions (NMJs) and control movement. Lower MNs are the primary target of incurable neuromuscular diseases such as spinal muscular atrophy (SMA). While MNs are the most affected cells in SMA, there is now abundant evidence that other tissues and cells are affected including skeletal muscles and Schwann cells. SMA is a monogenic disease caused mainly by mutations in the Survival of Motor Neuron 1 (SMN1) gene. Moreover, rare mutations in other genes have been also identified. The mechanisms underlying MN cell death in SMA, as well as the contribution of the skeletal muscle to the disease phenotype remain unresolved. Due to the neurological deficiencies a spinal cord biopsy would entail, it is impossible to obtain specific types of MNs and muscles to perform mechanistic studies from such patients. Thus, it becomes apparent that generation of both cell types from human induced pluripotent stem cells (iPSCs) becomes an absolute necessity to properly study the disease mechanisms and potential therapeutic approaches against SMA.


In this study, we propose to investigate the different rare SMA causing mutations to identify a common mechanism that leads to MN degeneration and muscular atrophy. To achieve this goal the successful candidate will benefit from the expertise of two different labs. In the Schülke lab, they have identified rare mutations in novel genes (such as IGHMBP2, TRIP4 and ASCC1) associated with SMA; they have extensively characterised the pathology of the disease in these patients and established fibroblast cell lines, which will be used to generate patient specific iPSCs. In the Gouti lab, they have recently established a novel human self-organizing neuromuscular (NM) organoid model, where spinal cord neurons are generated in parallel with skeletal muscle cells in 3D structures. These organoids can be maintained for several months in culture and recapitulate morphological and functional properties of the neuromuscular system: they contain functional NMJs supported by terminal Schwann cells. These NM organoids represent an exciting new in vitro platform to study the origin and mechanisms of SMA as they give us the unique opportunity to generate 3D models from human iPSCs carrying specific mutations and compare them with their isogenic controls. We expect that iPSC-based organoid models established during the course of this project, will not only give new insight into disease mechanisms but will also serve as a screening tool for potential therapies in the future.


We are looking for a highly motivated PhD student to contribute to the research area of neuromuscular disease modelling.
The project will be a collaboration between the Gouti Lab at Max Delbrück Center (MDC) and the Schülke Lab in Charite. The student will be based in the Gouti Lab at MDC and will work in close collaboration with a postdoctoral fellow. MDC provides state of the art research facilities and the opportunity to work in an interdisciplinary environment of research excellence.


Interested applicants should have previous experience in one or more of the mentioned research fields; stem cell biology, molecular biology, developmental biology, tissue engineering, live cell imaging and/or analysis of high-throughput data. Priority will be given to candidates with experience in human stem cell research and analysis of next generation sequencing data.




1. Gouti M*, Delile J, Stamataki D, Wymeersch F, Huang Y, Kleinjung J, Wilson V, Briscoe J*. (2017). A Gene Regulatory Network Balances Neural and Mesoderm Specification during Vertebrate Trunk Development. Dev Cell. 2017 May 8;41(3):243-261 * co-corresponding [PubMed]


2. Gouti M*, Tsakiridis A, Wymeersch FJ, Huang Y, Kleinjung J, Wilson V, Briscoe J*. (2014). In vitro generation of neuromesodermal progenitors reveals distinct roles for wnt signalling in the specification of spinal cord and paraxial mesoderm identity. PLoS Biol. 2014 Aug 26;12(8). * co-corresponding [PubMed]


3. Schottmann G, Jungbluth H, Schara U, Knierim E, Gonzalez SM, Gill E, Seifert F, Norwood F, Deshpande C, Au K von, Schuelke M*, Senderek J. Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy. Neurology 2015;84:523–31. *corresponding author [PubMed]


4. Grohmann K, Schuelke M, Diers A, Hoffmann K, Lucke B, Adams C, Bertini E, Leonhardt-Horti H, Muntoni F, Ouvrier R, Pfeufer A, Rossi R, Van Maldergem L, Wilmshurst JM, Wienker TF, Sendtner M, Rudnik- Schöneborn S, Zerres K, Hübner C. Mutations in the gene encoding immunoglobulin μ-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 2001;29:75–7. [PubMed]


5. Knierim E, Hirata H, Wolf NI, Morales-Gonzalez S, Schottmann G, Tanaka Y, Rudnik-Schöneborn S, Orgeur M, Zerres K, Vogt S, van Riesen A, Gill E, Seifert F, Zwirner A, Kirschner J, Goebel HH, Hübner C, Stricker S, Meierhofer D, Stenzel W, Schuelke M. Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures. Am J Hum Genet 2016;98:473–89. [PubMed]