Daniel Constam

Daniel Constam received his doctoral degree in Natural Sciences from ETH Zürich in the neuroimmunology group of Adriano Fontana (1993). For postdoctoral studies, he joined the laboratory of Elizabeth Robertson as an EMBO fellow at Harvard University to characterize proprotein convertase (PC) functions in mouse models of early embryogenesis (1994-1999). As an ISREC group leader (>2000) and Associate Professor at EPFL (>2007), he initially continued to study pluripotency and lineage differentiation during development and found that several secreted PCs jointly regulate cell-cell adhesion and TGFβ signaling pathways at the cross-roads of stem cell and cancer biology. To map the proteolytic activity of PCs and their relative distribution in exocytic or endocytic vesicles, his lab developed PC-specific FRET sensors for high resolution live imaging in normal cells and in tumour-host interactions. His studies on TGFβ signaling also identified the RNA-binding protein Bicc1 and its self-polymerization in membrane-less organelles as regulators of mRNA translation and cell metabolism that cooperate with primary cilia to prevent cystic growth in renal tubules and in pancreatic and bile ducts.

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Cell signaling

In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell sig

Stem cell

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the sa

Cellular differentiation

Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple t

BIO-392: Oncology

This course provides a comprehensive overview of the biology of cancer, illustrating the mechanisms that cancer cells use to grow and disseminate at the expense of normal tissues and organs.

BIO-611: Practical - Constam Lab

During development, cell fates are governed by multiple microenvironmental cues and their integration by specific signal transduction pathways. This course focuses on imaging of mechanosensory cilia or of molecules implicated in specific signal transduction events during mammalian embryogenesis.

Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex

Daniel Constam, Benjamin Marcel Daniel Rothé

Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand5 mRNA on the left side. We here examined how the fluid flow induces Dand5 mRNA decay. We found that the first 200 nucleotides in the 3 untranslated region (3 ' -UTR) of Dand5 mRNA are necessary and sufficient for the left-sided decay and to mediate the response of a 3 ' -UTR reporter transgene to Ca2+, the cation channel Pkd2, the RNA-binding protein Bicc1 and their regulation by the flow direction. We show that Bicc1 preferentially recognizes GACR and YGAC sequences, which can explain the specific binding to a conserved GACGUGAC motif located in the proximal Dand5 3 ' -UTR. The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node. These results suggest that Ca2+ currents induced by leftward fluid flow stimulate Bicc1 and Ccr4-Not to mediate Dand5 mRNA degradation specifically on the left side of the node. Questioning what regulates left-right asymmetry breaking in the mouse node: the authors identify a 200bp stretch of the Dand5 3'UTR where Bicc1 binds, and Cnot proteins downstream of calcium flow regulate the post-transcriptional regulation of Dand5 by Bicc1.

NATURE PORTFOLIO2021

Role of the RNA-binding protein Bicaudal-C1 and interacting factors in cystic kidney diseases

Daniel Constam, Céline Gagnieux, Lucía Carolina Leal Esteban, Benjamin Marcel Daniel Rothé

Polycystic kidneys frequently associate with mutations in individual components of cilia, basal bodies or centriolar satellites that perturb complex protein networks. In this review, we focus on the RNA-binding protein Bicaudal-C1 (BICC1) which was found mutated in renal cystic dysplasia, and on its interactions with the ankyrin repeat and sterile a motif (SAM)-containing proteins ANKS3 and ANKS6 and associated kinases and their partially overlapping ciliopathy phenotypes. After reviewing BICC1 homologs in model organisms and their functions in mRNA and cell metabolism during development and in renal tubules, we discuss recent insights from cell-based assays and from structure analysis of the SAM domains, and how SAM domain oligomerization might influence multivalent higher order complexes that are implicated in ciliary signal transduction.

2020

A novel cell-based sensor detecting the activity of individual basic proprotein convertases

Daniel Constam, Stefan Kunz

The basic proprotein convertases (PCs) furin, PC1/3, PC2, PC5/6, PACE4, PC4, and PC7 are promising drug targets for human diseases. However, developing selective inhibitors remains challenging due to overlapping substrate recognition motifs and limited structural information. Classical drug screening approaches for basic PC inhibitors involve homogeneous biochemical assays using soluble recombinant enzymes combined with fluorogenic substrate peptides that may not accurately recapitulate the complex cellular context of the basic PC-substrate interaction. Herein we report basic PC sensor (BPCS), a novel cell-based molecular sensor that allows rapid screening of candidate inhibitors and their selectivity toward individual basic PCs within mammalian cells. BPCS consists of Gaussia luciferase linked to a sortilin-1 membrane anchor via a cleavage motif that allows efficient release of luciferase specifically if individual basic PCs are provided in the same membrane. Screening of selected candidate peptidomimetic inhibitors revealed that BPCS can readily distinguish between general and selective PC inhibitors in a high-throughput screening format. The robust and cost-effective assay format of BPCS makes it suitable to identify novel specific small-molecule inhibitors against basic PCs for therapeutic application. Its cell-based nature will allow screening for drug targets in addition to the catalytically active mature enzyme, including maturation, transport, and cellular factors that modulate the enzyme's activity. This broadened 'target range' will enhance the likelihood to identify novel small-molecule compounds that inhibit basic PCs in a direct or indirect manner and represents a conceptual advantage.

WILEY2019