Name R. Jeroen Pasterkamp
Department of Neuroscience and Pharmacology
Section Neurodevelopment
Function Assistant Professor and coordinator section Neurodevelopment
E-mail:
r.j.pasterkamp@umcutrecht.nl tel: +31-88-7568831
Research group
Youri Adolfs (research technician)
Koushik Chakrabarty (postdoc)
Alwin Derijck (postdoc)
Katsumi Fumoto (postdoc)
Rou-Afza Gunput (graduate student)
Anita Hellemons (research technician)
Bart Jongbloets (graduate student)
Francesca Morello (graduate student)
Asheeta Prasad (graduate student)
Ewoud Schmidt (graduate student)
Dianne van den Heuvel (graduate student)
Susan van Erp (graduate student)
Yeping Zhou (graduate student)
Title research line
Neural Circuit Development and Disease
Summary research Disturbed neuronal connectivity is a hallmark of many neural disorders. For example, abnormal wiring of the brain during development is believed to contribute to pathophysiology of disorders such as schizophrenia and autism, while neurodegenerative disorders including Parkinson's disease and ALS are characterized by a marked loss of neuronal connections. To better understand and treat these situations of perturbed neuronal connectivity further insight is needed into the mechanisms that normally control nervous system wiring. The aim of our research is twofold: 1) to determine how neuronal connections are formed during development at the molecular, cellular and systems level, and 2) how and why neuronal connections are lost in ALS.
Molecular mechanisms of axon guidance One of the most challenging problems in biology is to understand how the billions of neurons in the mammalian nervous system “wire up” to form functional neural circuits that underlie all behavior. This has been one of the most intensely studied areas of developmental neurobiology in the past decade, and a number of important proteins have been identified that instruct axons to project to their specific target regions. These so-called axon guidance proteins are detected by a highly motile and sensitive structure at the leading tip of every growing axon, the growth cone. Receptor complexes at the growth cone cell surface detect axon guidance proteins and consequently trigger intracellular signal transduction cascades that infringe upon the cytoskeleton and induce growth cone/axon steering. Guidance proteins can act as attractants or repellents, that is, either directing axons towards a specific structure or preventing them from entering inappropriate regions. Furthermore, they exist as membrane-associated cues acting at short ranges or as secreted agents with longer-range effects. Different families of guidance proteins and receptors have been identified, including i) semaphorins and their neuropilin and plexin receptors, ii) netrins and their DCC and UNC5 receptors, iii) Slits and their Robo receptors, iv) ephrins and their Eph receptors, and v) repulsive guidance molecules (RGMs) and their neogenin receptor. More recently, additional protein families previously recognized for other functions such as Wnts have been implicated in axon guidance. Although considerable progress has been made in defining the ligand, receptor and, to a certain extent, cytosolic signal transduction proteins involved in axon guidance, the mechanisms by which the expression, localization and function of these proteins is controlled to fine-tune and diversify the axon guidance process remain poorly defined. Several projects in the lab focus on revealing novel signaling and regulatory mechanisms in axon guidance using cutting-edge technology such as LNA array technology, high-throughput and live cell microscopy, in utero electroporation, functional proteomics approaches, mouse genetics, FACS, biochemistry, and molecular cell biology. Examples of this research include the identification of proteins that can terminate axon guidance receptor expression or microRNAs that regulate their expression.
Pathogenic mechanisms in ALS
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease affecting some 50,000 individuals at any time in Europe, and causing around 10,000 deaths each year. ALS is characterized by progressive degeneration of motor neurons in brain and spinal cord leading to muscle weakness. ALS can occur in any individual at anytime in adulthood. Initial manifestions are weakness of limbs, or weakness in the bulbar region leading to abnormalities of speech, swallowing difficulties and facial weakness. The patient becomes paralyzed and dies as the result of respiratory failure. The median survival is 3 years after onset of symptoms. There is no cure for ALS. The only available drug (Riluzole) is marginally effective in extending the lifespan of ALS patients with 3 to 6 months. Novel treatment options are needed for this disabling and fatal disease. The lack of treatment in ALS can be attributed to an absence of validated therapeutic targets reflecting inadequate understanding of disease mechanisms. Elucidating the ALS pathogenic mechanism is therefore essential to pave the road for therapeutic interventions. Several projects in the lab focus on further unravelling the molecular mechanisms which are disturbed in ALS with a strong focus on ALS-associated proteins implicated in RNA processing such as FUS or TDP-43 or in synaptic function such as Munc13-1. The molecular basis of ALS pathology is studied in collaboration with the Dept. Neurology, UMC Utrecht (Prof Leonard van den Berg) using molecular cell biology, mouse and zebrafish genetics, cell biology and stem cell technology.
Publications 1. Derijck AAH, Van Erp S, Pasterkamp RJ (2010) Semaphorin signaling: Molecular switches at the midline. Trends Cell Biol, in press.
2. Kolk SM, Gunput RA, Tran TS, Van den Heuvel DM, Prasad AA, Hellemons AJ, Adolfs Y, Ginty DD, Kolodkin AL, Burbach JP, Smidt MP, Pasterkamp RJ (2009) Semaphorin3F is a bifunctional guidance cue for dopaminergic axons and controls their fasciculation, channeling, rostral growth, and intracortical targeting. J Neurosci 29: 12542-12557.
3. Van Es MA, Veldink JH et al. (2009) Genome-wide association study identifies 19p13.3 (UNC13A) and 19p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genetics 41:1083-1087.
4. Suzuki K, Okuno T, Yamamoto M, Pasterkamp RJ, Takegahara N, Takamatsu H, Kitao T, Takagi J, Rennert PD, Kolodkin AL, Kumanogoh A, Kikutani H (2007) Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature 446:680-684.
5. Pasterkamp RJ, Peschon JJ, Spriggs MK, Kolodkin AL (2003) Semaphorin7A promotes axon outgrowth through integrins and MAPKs. Nature (leading article) 424:398-405.