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Del Toro D*, Ruff T*, Cederfjäll E, Villalba A, Seyit-Bremer G, Borrell V, Klein R.
* co-first-author
Cell, 2017, 169, 621-635.

Regulation of Cerebral Cortex Folding by Controlling Neuronal Migration via FLRT Adhesion Molecules.

The folding of the mammalian cerebral cortex into sulci and gyri is thought to be favored by the amplification of basal progenitor cells and their tangential migration. Here, we provide a molecular mechanism for the role of migration in this process by showing that changes in intercellular adhesion of migrating cortical neurons result in cortical folding. Mice with deletions of FLRT1 and FLRT3 adhesion molecules develop macroscopic sulci with preserved layered organization and radial glial morphology. Cortex folding in these mutants does not require progenitor cell amplification but is dependent on changes in neuron migration. Analyses and simulations suggest that sulcus formation in the absence of FLRT1/3 results from reduced intercellular adhesion, increased neuron migration, and clustering in the cortical plate. Notably, FLRT1/3 expression is low in the human cortex and in future sulcus areas of ferrets, suggesting that intercellular adhesion is a key regulator of cortical folding across species.


Folds in the human brain enlarge the surface of this important processing organ and in this way create more space for higher functions including thought and action. However, certain species of mammals exist whose brains have smooth surfaces, for example mice. Scientists from the Max Planck Institute of Neurobiology in Martinsried have discovered a previously unknown mechanism for brain folding. Young neurons, which migrate to the cortex during the development of a smooth-surfaced brain, have so-called FLRT receptors on their cell surface. These ensure a certain degree of adhesion between the cells and regular migratory behaviour which favours the formation of a smooth brain surface. Compared to the mouse brain, in the human brain FLRTs are much less abundant. If the expression of FLRTs in the mouse brain is reduced experimentally, folds similar to those found in the human brain form. These findings provide new insights into the evolution of smooth and folded mammalian brains.

The human brain has many grooves and furrows which enlarge the brain surface considerably compared to that of a smooth brain. Homo sapiens is not the only species to form folds in the brain, however. It is likely that the ancestral mammal, which lived around 200 million years ago, also had a folded brain. Over the course of evolution, various mammalian species lost their brain folds again. Hence mice and rats, for example, have brains with smooth surfaces.

“The evolutionary success of these and other animal species with smooth brains shows that having a brain without folds is not necessarily disadvantageous and works well for these species,” explains Rüdiger Klein, a Director at the Max Planck Institute of Neurobiology. “We were interested in how brain folds actually arise.”

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Prytuliak R, Volkmer M, Meier M, Habermann BH.
Nucleic Acids Res, 2017, [Epub ahead of print].

HH-MOTiF: de novo detection of short linear motifs in proteins by Hidden Markov Model comparisons.

Short linear motifs (SLiMs) in proteins are self-sufficient functional sequences that specify interaction sites for other molecules and thus mediate a multitude of functions. Computational, as well as experimental biological research would significantly benefit, if SLiMs in proteins could be correctly predicted de novo with high sensitivity. However, de novo SLiM prediction is a difficult computational task. When considering recall and precision, the performances of published methods indicate remaining challenges in SLiM discovery. We have developed HH-MOTiF, a web-based method for SLiM discovery in sets of mainly unrelated proteins. HH-MOTiF makes use of evolutionary information by creating Hidden Markov Models (HMMs) for each input sequence and its closely related orthologs. HMMs are compared against each other to retrieve short stretches of homology that represent potential SLiMs. These are transformed to hierarchical structures, which we refer to as motif trees, for further processing and evaluation. Our approach allows us to identify degenerate SLiMs, while still maintaining a reasonably high precision. When considering a balanced measure for recall and precision, HH-MOTiF performs better on test data compared to other SLiM discovery methods. HH-MOTiF is freely available as a web-server at


The cerebellum

In order to successfully survive in a changing environment, animals must be able to combine sensory inputs with information about their own movement. Complex motor behaviors, like walking or riding a bike, would be difficult to perform without feedback signals such as the sense of the feet touching the ground or the perception of movement with respect to the world. Scientists from the Max Planck Institute of Neurobiology in Martinsried use zebrafish as a simple vertebrate model to study how different kinds of sensory and motor information map onto the cerebellum. Their recent study shows that scientists need to rethink about how this large and important part of the brain of all vertebrates, including humans, works.

In a recent study published in the journal Current Biology, Laura Knogler and her colleagues from the Portugues group at the Max Planck Institute of Neurobiology used small translucent larval zebrafish to record cerebellar activity. For the first time, scientists were thus able to record from all the granule cells in the cerebellum of an awake, behaving vertebrate. As Laura explained: “This is possible because the brains of these fish are small, less than 1 mm cubed, and because we can express fluorescent proteins in their brains that light up when neurons are active.” When asked to summarize the main findings, Laura continues: “We were surprised to see that a large fraction of the cerebellar granule cells, nearly 50%, were active when we presented simple sensory stimuli such as light flashes or moving scenes. Some neurons were only active when the fish swam.”

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the social network of immune cells

Facebook, Instagram, Twitter – nowadays, good social networking and communication is more important than ever. The immune system also resembles a large social network, as shown by Felix Meissner and his team in the Experimental System Immunology Research Group at the Max Planck Institute of Biochemistry in Martinsried. With the help of proteomics they deciphered the messages exchanged between immune cells responsible for protecting us  against diseases. In doing so, they have discovered complex cellular communication structures and previously unknown connections between various cell types. Their research findings were published in the journal Nature Immunology.

Social networks such as Facebook now connect people around the globe, for the exchange of countless messages and pieces of information every day. Some people prefer to use social networks passively, only reading messages, while others have a strong need to communicate with others and tend to send out a large volume of information. The cells of our immune system work in a similar manner. When cells wish to communicate with each other, they emit messengers, unique signal molecules, which are detected by other cells via cell surface receptors. These messengers disseminate information throughout the body to control immune reactions against pathogens. Some cell types are more communicative than others. “Innate immune cells such as macrophages are real chatterboxes,” Meissner says.

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Schopf FH, Biebl MM, Buchner J.
Nat Rev Mol Cell Biol, 2017, [Epub ahead of print].

The HSP90 chaperone machinery.

The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.


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Zhang X, Schnorrer F.
FEBS J. 2017, 284, 1178-1181.

AIDing-targeted protein degradation in Drosophila.

Conditional protein depletion is highly desirable for investigating protein functions in complex organisms. In this issue, Bence and colleagues combined auxin-inducible degradation with CRISPR, establishing an elegant tool to control protein levels. They achieve precise spatio-temporal control of protein degradation during Drosophila oogenesis and early embryogenesis by combining suitable GAL4 drivers (spatial control) with auxin feeding protocols (temporal control).


Biochemist Karl-Peter Hopfner studies how cells detect and repair the damage to their DNA. His work has now won him Germany’s most prestigious prize for research.

The magnitude of the repair job is mind-boggling: Every day, around 100,000 of the building-blocks (‘bases’) in the genomic DNA of virtually every cell in our bodies suffer damage, and are chemically altered. Left unrepaired, these alterations in our genetic material can kill cells, induce the development of tumors, precipitate premature ageing and cause congenital diseases when they occur in germ cells. However, evolution has equipped cells with highly efficient mechanisms for the repair of DNA damage.

At LMU’s Gene Center Karl-Peter Hopfner is studying the complex molecular machines that make it possible for cells to locate adventitious damage and enzymatic errors and repair or remove the modified bases. With the aid of high-resolution methodologies such as X-ray crystallography and cryo-electron microscopy, Hopfner elucidates the structures and modes of action of the molecular machines that tackle this gargantuan task. In order to develop effective treatments for disorders that result when these systems themselves are defective, detailed knowledge of their molecular form is an essential prerequisite. The Deutsche Forschungsgemeinschaft (DFG) has now acknowledged Karl-Peter Hopfner’s contributions to research by awarding him a Leibniz Prize.

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Borst 2017

In order to react to changes in the environment in good time, the brain must analyze the signals it receives from the eyes rapidly and accurately. For example, the ability to recognise the direction in which an approaching car is moving is vital to the survival of modern humans in cities. Using the brain of the fruit fly Drosophila as a model, scientists from the Max Planck Institute of Neurobiology study how the brain extracts this essential motion information. They have now described in detail the cells that enable downstream neurons to recognize the direction of movement. Interestingly, the characteristics of these input cells exactly match to a motion detector model they recently proposed. In addition, the cells alter their characteristics according to the animals’ state: when the fly is active, the cells respond faster to light stimuli.

Humans perceive their environment mainly through their eyes. The ability to recognize movements and their direction is something that seems almost trivial and automatic to us. However, this information has to be processed in the brain as the light-sensitive sensory cells of the retina can only register changes in contrast. The direction of a movement can only be calculated through the comparison of neighbouring signals. Various models exist for these calculations. Alexander Borst and his team at the Max Planck Institute of Neurobiology study the extent to which these models can be applied to the brain’s neuronal circuitry. Their test subject is the fruit fly Drosophila, a master of motion perception.

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Although all cells in an organism contain the same genes, only some of the genes are activated in a given cells and others remain inactive. Genes coil around histone proteins in the form of DNA threads. If a gene has to remain inactive, its histones are marked by the PRC2 enzyme so that this gene is locked down and cannot be read. When cells divide and the genes are copied, these histone marks must be placed again, at exactly the same location. The mechanism that enables transmission of this information has now been explained by Jürg Müller from the Max Planck Institute of Biochemistry in Martinsried in a study published in the journal Science.

In animals and plants, the genomic DNA in the cell nucleus is wrapped around small proteins known as histones. Jürg Müller, Leader of the Biology of Chromatin Research Group at the MPI of Biochemistry explains: “The DNA is like a big library of books. Each book contains the instruction manual for making a protein. Although the same DNA library is present in all cells, some of the books are ‘sealed’, so they cannot be read. A muscle cell requires other protein-building instructions than an intestinal cell.” An essential mechanism to prevent the expression of genes relies on the chemical marking of histone proteins to permanently “lock down” genes. In the current study, Müller and his team examined how such gene locks are transmitted during cell division. Histones play a key role in determining how accessible a gene is. When genes need to be permanently locked down, their histones are chemically modified by the enzyme PRC2. “If we imagine the histones as the binder of the book, PRC2 helps to seal that book and prevent that it gets opened and read,” explains Müller. 

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