A fundamental issue during development is the appropriate formation of connections in the brain. Accuracy of these events is critical for the correct functioning of the brain, including the processes involved in memory, learning, perception and behaviour.
We are interested in the molecular mechanisms underlying this establishment of neural connectivity during development and its maintenance at later stages in life. A particular focus is the molecular control of axon pathfinding mechanisms and the establishment of specific synaptic interactions between subpopulations of neurons. We use the mammalian visual system as a model, due to its easy accessibility for manipulations, the highly regular arrangement of specific subsets of neurons and the generation of defined orderly circuits within the retina or axon projections from the eye to different brain targets.
The major goals of our laboratory are to:
Discover the molecular network necessary to establish neural connectivity from the eye to the brain and the formation of neural maps.
Molecularly specify subtypes of neurons and the formation of specific connections with their appropriate synaptic partners.
Develop bridges between these developmental strategies and the mechanisms necessary to re-establish connectivity in the brain after injury or disease.
Role of microRNAs in axon pathfinding
MicroRNAs are small non-coding RNA molecules that are encoded endogenously in the genome. They are transcribed as precursors and subsequently processed in the nucleus and cytoplasm to their mature form of 21-25 nucleotides in length. Binding to the mRNA of target genes leads to translational repression of the degradation of the messenger. MicroRNAs are highly conserved through evolution and have been implicated in a variety of biological processes, ranging from cell differentiation to synaptogenesis. However their role in axon pathfinding and neural connectivity is less clear.
In this project we are analyzing the role of miRNAs during the formation of the visual projection from the eye to the brain and the subsequent generation of the visuotopic map. Our results show, that these non-coding RNAs play an important role for axon pathfinding at the optic chiasm (Pinter & Hindges, 2010). We are currently extending these studies and analyse retinal projections to their midbrain targets in mice lacking miRNAs. We are also working on the identification of the individual miRNAs and their targets that are involved in these processes.
The retina consists of seven principal cell types that are generated in a chronological sequence from retinal progenitor cells in during eye development. However, these different cell types can be further divided into specific subclasses, spread across the retina. Subclass-specific circuits are present to separate visual information into separate channels, such as orientation, movement, light intensity etc.
A feature of such individual circuits, for example between retinal ganglion cells and bipolar or amacrine cells is the organisation of their synaptic interactions in precise vertical stacks in the inner plexiform layer (IPL) of the retina. We have identified several molecules that are expressed by subtypes of retinal ganglion cells and that are localised specifically in individual IPL stacks. This suggests that they are part of individual visual circuits. With this project we are analysing the roles of these molecules in the formation of such subtype-specific synapses localised in defined laminas of the IPL. Furthermore we will characterise the physiological properties of the marked retinal ganglion cells to identify their function.
Establishing the visual topographic map
Topographic maps are a fundamental organisational feature of most axonal connections in the brain. The dominant model for studying map development is the projection from the eye to the midbrain target, the superior colliculus in mammals or their non-mammalian homologue, the optic tectum. The precise spatial ordering of axonal arborizations of retinal ganglion cells (RGCs) maps the visual world along two sets of orthogonally oriented axes: the temporal-nasal (TN) axis of the retina along the anterior-posterior (AP) axis of the tectum, and the dorsal-ventral (DV) retinal axis along the lateral-medial (LM) tectal axis.
We have identified previouosly that interactions between EphB receptors and their ephrin-B ligands are crucial for the correct generation of the topographic map along the LM collicular axis (Hindges et al., 2002). The results however indicated that additional molecular activities play an important role.
In this project we are analysing candidate genes that we have identified using an functional genomics screen, in their role to control i) the ingrowth of axons into the superior colliculus, ii) the formation of appropriate axonal branches and iii) the precise refinement of the termination zone.