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(Beretta et al., 2017)

That's me:

After a Master thesis in Virology at Göttingen University, I started my "fishy" research journey at the Max-Planck Institute in Göttingen and the EMBL-Heidelberg during my PhD working on eye and brain development using the Medakafish. I moved to UCL London to learn working with zebrafish and to investigate left-right brain asymmetries during my postdoctoral period. This topic still fascinated me having been appointed as a principal investigator at Heidelberg University and even now in my group at Trento University. The Medaka though never left my side and we are now combining my expertise to elucidate why our brain hemispheres are so different in shape and function. Intriguingly, a number of genes we discover are RISK genes for autism, schizophrenia and depression. Is there a connection??? We have an exceptionally friendly and interactive lab-atmosphere, always helping each other and working together to reach our goals. 

Want to have a quick look on some of the things we are doing? Here is a lab tour (in Italian) recorded for a major public outreach event at MUSE in 2021 (many thanks to the MUSE recording team!).

Quick check our main topic:

RESEARCH INTERESTS

POSITIONS

(Some) COLLABORATORS

  • Francesco Argenton, Enrico Moro: Wnt-reporter transgenic zebrafish lines, University Padova, Italy

  • Felix Loosli: Medaka mutants and strains, KIT Karlsruhe, Germany

  • Giovanni Piccoli: Disease gene candidates, University of Trento, Italy

  • Lucia Poggi: Imaging, University of Trento, Italy

  • Steffen Scholpp: Wnt signaling in zebrafish, Exeter University, UK

  • Veit Riechmann: Gene function in fly, Heidelberg University, Germany

  • Steve Wilson: Tools and resources for zebrafish, UCL London, UK

  • Jochen Wittbrodt: Medaka resources, Heidelberg University, Germany

UNIVERSITY TRAINING

2018             Habilitation in Physiology (Fascia II), Italy

2017             Habilitation in Comparative Anatomy and                                       Cell Biology (Fascia I and Fascia II), Italy

2017             Habilitation in Genetics (Fascia II), Italy

2017             Habilitation in Applied Biology (Fascia II), Italy

2015             Habilitation and Venia Legendi in Cell- and                                     Molecular Biology, Heidelberg University,                                     Germany

2011             Certificate for University Didactics, Heidelberg                               University, Germany

1999             Dr. rer. nat., MPI Göttingen, EMBL-Heidelberg,                             Heidelberg University, Germany

1995             Master of Biology, Göttingen University, Germany

1989 - 1995  Studies of Biology, Göttingen University, Germany

Translational Neurosciences I

Left-right brain asymmetries - genetics and function

2017 - 2020

Trento University, Italy

Assistant Professor working on mental disorders, brain asymmetry and axis formation

Development

Axis formation and comparative genetics

Models

Zebrafish and Medakafish. In collaboration also Xenopus, Drosophila, mouse and cell culture

Genetics

Main focus is the Wnt/beta-catenin pathway

2009 - 2017

Heidelberg University, Germany

PI working on Wnt in brain asymmetry and axis formation

2002 - 2008

University College London, UK

Postdoc on Wnt in left-right brain asymmetries

2000 - 2002

EMBL-Heidelberg, Germany

Postdoc on Six3 in eye development

1996 - 1999

MPI Göttingen and EMBL-Heidelberg, Germany

PhD Thesis on FGF in eye and brain development

Translational Neurosciences II

Linking genes, neural circuits and psychiatric disorders

2020 - present

Trento University, Italy

Associate Professor 

SELECTED RECENT ARTICLES

Habicher, J.; Sanvido, I.; Bühler, A.; Sartori, S.; Piccoli, G.; Carl, M. (2024). The risk genes for neuropsychiatric disorders negr1 and opcml are expressed throughout zebrafish brain development. Genes, 15:363. https://doi.org/10.3390/genes15030363

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Agostini, C., Bühler, A., et al., (2022). Conserved and diverged asymmetric gene expression in the brain of teleosts. Frontiers in Cell and Developmental Biology, doi: 10.3389/fcell.2022.1005776.

Bühler, A. and Carl, M. (2021). Zebrafish tools for deciphering habenular network-linked mental disorders. Biomolecules, 11(2):324. DOI: 10.3390/biom11020324 

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Guglielmi, L., et al., 2020. Temporal control of Wnt signaling is required for habenular neuron diversity and brain asymmetry. Development, 147(6). 

DOI: 10.1242/dev.182865

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Abstract

The immunoglobulin LAMP/OBCAM/NTM (IgLON) family of cell adhesion molecules comprises five members known for their involvement in establishing neural circuit connectivity, fine-tuning, and maintenance. Mutations in IgLON genes result in alterations in these processes and can lead to neuropsychiatric disorders. The two IgLON family members NEGR1 and OPCML share common links with several of them, such as schizophrenia, autism, and major depressive disorder. However, the onset and the underlying molecular mechanisms have remained largely unresolved, hampering progress in developing therapies. NEGR1 and OPCML are evolutionarily conserved in teleosts like the zebrafish (Danio rerio), which is excellently suited for disease modelling and large-scale screening for disease-ameliorating compounds. To explore the potential applicability of zebrafish for extending our knowledge on NEGR1- and OPCML-linked disorders and to develop new therapeutic strategies, we investigated the spatio-temporal expression of the two genes during early stages of development. negr1 and opcml are expressed maternally and subsequently in partially distinct domains of conserved brain regions. Other areas of expression in zebrafish have not been reported in mammals to date. Our results indicate that NEGR1 and OPCML may play roles in neural circuit development and function at stages earlier than previously anticipated. A detailed functional analysis of the two genes based on our findings could contribute to understanding the mechanistic basis of related psychiatric disorders.

Abstract

Morphological left-right brain asymmetries are universal phenomena in animals. These features have been studied for decades, but the functional relevance is often unclear. Studies from the zebrafish dorsal diencephalon on the genetics underlying the establishment and function of brain asymmetries have uncovered genes associated with the development of functional brain asymmetries. To gain further insights, comparative studies help to investigate the emergence of asymmetries and underlying genetics in connection to functional adaptation. Evolutionarily distant isogenic medaka inbred lines, that show divergence of complex traits such as morphology, physiology and behavior, are a valuable resource to investigate intra-species variations in a given trait of interest. For a detailed study of asymmetry in the medaka diencephalon we generated molecular probes of ten medaka genes that are expressed asymmetrically in the zebrafish habenulae and pineal complex. We find expression of eight genes in the corresponding brain areas of medaka with differences in the extent of left-right asymmetry compared to zebrafish. Our marker gene analysis of the diverged medaka inbred strains revealed marked inter-strain size differences of the respective expression domains in the parapineal and the habenulae, which we hypothesize may result from strain-specific gene loss. Thus, our analysis reveals both inter-species differences but also intra-species plasticity of gene expression in the teleost dorsal diencephalon. These findings are a starting point showing the potential to identify the genetics underlying the emergence and modulations of asymmetries. They are also the prerequisite to examine whether variance in habenular gene expression may cause variation of behavioral traits.

Abstract

The prevalence of patients suffering from mental disorders is substantially increasing in recent years and represents a major burden to society. The underlying causes and neuronal circuits affected are complex and difficult to unravel. Frequent disorders such as depression, schizophrenia, autism, and bipolar disorder share links to the habenular neural circuit. This conserved neurotransmitter system relays cognitive information between different brain areas steering behaviors ranging from fear and anxiety to reward, sleep, and social behaviors. Advances in the field using the zebrafish model organism have uncovered major genetic mechanisms underlying the formation of the habenular neural circuit. Some of the identified genes involved in regulating Wnt/beta-catenin signaling have previously been suggested as risk genes of human mental disorders. Hence, these studies on habenular genetics contribute to a better understanding of brain diseases. We are here summarizing how the gained knowledge on the mechanisms underlying habenular neural circuit development can be used to introduce defined manipulations into the system to study the functional behavioral consequences. We further give an overview of existing behavior assays to address phenotypes related to mental disorders and critically discuss the power but also the limits of the zebrafish model for identifying suitable targets to develop therapies.

Abstract

Precise temporal coordination of signaling processes is pivotal for cellular differentiation during embryonic development. A vast number of secreted molecules are produced and released by cells and tissues, and travel in the extracellular space. Whether they induce a signaling pathway and instruct cell fate, however, depends on a complex network of regulatory mechanisms, which are often not well understood. The conserved bilateral left-right asymmetrically formed habenulae of the zebrafish are an excellent model for investigating how signaling control facilitates the generation of defined neuronal populations. Wnt signaling is required for habenular neuron type specification, asymmetry and axonal connectivity. The temporal regulation of this pathway and the players involved have, however, have remained unclear. We find that tightly regulated temporal restriction of Wnt signaling activity in habenular precursor cells is crucial for the diversity and asymmetry of habenular neuron populations. We suggest a feedback mechanism whereby the tumor suppressor Wnt inhibitory factor Wif1 controls the Wnt dynamics in the environment of habenular precursor cells. This mechanism might be common to other cell types, including tumor cells.

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