Center for Molecular Medicine Cologne

Gehring, Niels - C 05

Function of nonsense-mediated mRNA decay in brain development and neurological disease


Nonsense-mediated mRNA decay (NMD) is a crucial quality control mechanism in eukaryotic cells that safeguards the fidelity of protein synthesis. NMD selectively eliminates messenger RNAs (mRNAs) that carry premature translation termination codons, commonly referred to as NMD substrates. Thereby NMD prevents the production of truncated polypeptides that may have toxic effects on cellular functions. The process of NMD is executed by a complex machinery composed of RNA-binding proteins and NMD factors that work together to recognize, and degrade NMD substrates.
Mutations in genes involved in the NMD mechanism have been linked to neurodevelopmental disorders (NDDs). For example, pathogenic variants in the gene encoding the NMD activator UPF3B have been identified as a cause of X-linked intellectual disability (ID). Similarly, deletions of genomic regions containing the gene for the NMD factor UPF2 have been associated with ID and other NDDs. Furthermore, point mutations in the NMD regulators SMG8 and SMG9 have been linked to cardiac and cerebral malformations. Despite these observations, the precise mechanisms by which NMD mutations contribute to NDDs remain unclear.
Here, we propose to dissect the function of NMD during brain development. We will use hiPSCs to knock out UPF3B by genome editing and/or alter the expression of the paralog UPF3A, which modulates the disease phenotype in patients with UPF3B mutations. In addition, we will up- and downregulate the global NMD efficiency in hiPSCs by different genetic interventions and pharmacological treatments.
As one main approach we will use the generation of brain organoids, which provide an excellent model system to investigate the mechanisms of brain development, including the role of NMD. We will investigate the effects of different NMD manipulations on the formation, composition, and complexity of brain organoids.
Our project aims to dissect the function of NMD during brain development and shed light on the mechanisms by which mutations in NMD genes contribute to NDDs. By studying the molecular and cellular effects of NMD inhibition and activation, we hope to identify potential therapeutic targets for NDDs that are linked to NMD dysfunction.

Figure 1

Clinical Relevance

Between 1 and 5% of children worldwide are diagnosed with various neurodevelopmental disorders (NDDs). Genetic studies suggest a high heritability, but the clinical symptoms of NDDs are often heterogeneous. To diagnose and accelerate the treatment of genetic NDDs, it is essential to define the full spectrum of defective molecular pathways. Therefore, our project aims to study the role of nonsense-mediated decay (NMD) in brain development to dissect the molecular basis of NMD-dependent NDDs.

Linder B, Fischer U, Gehring NH (2015) mRNA metabolism and neuronal disease. FEBS Lett 589: 1598-1606


  • - differentiate human induced pluripotent stem cells (hiPSCs) into cerebral organoids to mimic early human brain development
  • - manipulate expression levels of various genes involved in the quality control pathway nonsense-mediated e.g. by genome editing or transgene insertion in hiPSCs
  • -  modulate NMD activity by either decreasing or increasing its efficiency either on hiPSC level or in the organoids
  • - investigate the effects of the above-mentioned alterations on the formation, composition and complexity of neuronal cells and cerebral organoids
  • - a variety of methods will be used to determine the NMD-regulated transcriptome of human brain organoids
Figure 2

Fig.2: Modulating NMD activity in brain organoids and analyzing the effects.
Top: Representative images showing the formation, expansion, and maturation of brain organoids generated in the Gehring lab.
Bottom: Brain organoids will be generated from hiPSCs using the methodology described above. Different treatments and genetic interventions will be applied to modulate global NMD activity, as depicted schematically. The structure and composition of the organoids will be compared using transcriptomic and proteomic analyses, imaging techniques, and functional assays.

  • Clerici M, Deniaud A, Boehm V, Gehring NH, Schaffitzel C, Cusack S (2014) Structural and functional analysis of the three MIF4G domains of nonsense-mediated decay factor UPF2. Nucleic Acids Res 42: 2673-2686
  • Gehring NH, Neu-Yilik G, Schell T, Hentze MW, Kulozik AE (2003) Y14 and hUpf3b form an NMD-activating complex. Mol Cell 11: 939-949
  • Kunz JB, Neu-Yilik G, Hentze MW, Kulozik AE, Gehring NH (2006) Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA 12: 1015-1022
  • Linder B, Fischer U, Gehring NH (2015) mRNA metabolism and neuronal disease. FEBS Lett 589: 1598-1606
  • Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Vandeleur L, Smith R, Shoubridge C, Edkins S, Stevens C et al (2007) Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet 39: 1127-1133
  • Wallmeroth D, Lackmann JW, Kueckelmann S, Altmuller J, Dieterich C, Boehm V, Gehring NH (2022) Human UPF3A and UPF3B enable fault-tolerant activation of nonsense-mediated mRNA decay. EMBO J 41: e109191
Prof. Dr. Niels Gehring CMMC Cologne
Prof. Dr. Niels Gehring

Institute for Genetics - Center of Molecular Biosciences

CMMC - PI - C 05

+49 221 470 3873

Institute for Genetics - Center of Molecular Biosciences

Zülpcher Str. 47a

50674 Cologne

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Group Members

Dr. Volker Böhm
PhD students:
Damaris Wallmeroth
Sabrina Kückelmann
André Müller

Master student:
Sophie Theunissen
Silke Modersohn
Juliane Hancke
Vanessa Paszella