Person: Kostadinov, Dimitar Vladimirov
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Kostadinov
First Name
Dimitar Vladimirov
Name
Kostadinov, Dimitar Vladimirov
2 results
Search Results
Now showing 1 - 2 of 2
Publication Mechanism and Function of Dendritic Self-Avoidance and Self/non-Self Discrimination in the Mammalian Nervous System(2015-06-29) Kostadinov, Dimitar Vladimirov; Engert, Florian; Ginty, David; Murthy, Venkatesh; Berson, DavidDendritic and axonal arbors of many neuronal types exhibit self-avoidance, a phenomenon in which branches repel each other. This process ensures that individual neurons cover all parts of their territory uniformly. Some neurons that self-avoid overlap with neighbors of the same type, suggesting that nominally identical neurons are immune to each other’s repellent forces, a phenomenon called self/non-self discrimination. Here, I describe the roles of the 22 clustered gamma-Protocadherin (Pcdhg) recognition molecules in dendritic self-avoidance and self/non-self discrimination of mammalian neurons, and the roles of these phenomena in a retinal circuit. First, I present studies showing that Pcdhgs are necessary for dendritic self-avoidance and self/non-self discrimination of retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Using loss and gain of function experiments, we showed that no single Pcdhg isoform is necessary and any Pcdhg isoform is sufficient to mediate self-avoidance. However, forcing neighboring SACs to express a single Pcdhg decreases their overlap. Thus, Pcdhg diversity is necessary for SACs to avoid their own dendrites, but interact with their neighbors (self/non-self discrimination). Second, I describe the roles of self-avoidance and self/non-self discrimination in the function of a retinal direction-selective circuit that depends on SACs. Dendrites of SACs compute directional motion and endow classes of retinal ganglion cells with this property by inhibiting them asymmetrically during visual motion. In addition, SACs form inhibitory synapses in order to sharpen each other’s direction-selectivity. I present findings that elucidate the roles self-avoidance and self/non-self discrimination in the function of this direction-selective circuit: (1) In the absence of self-avoidance, SACs form synapses with their own dendrites. (2) In the absence of self/non-self discrimination, SACs form few synapses with each other, (3) Loss of either self-avoidance or self/non-self discrimination degrades directional responses of ganglion cells. Lastly, I describe initial efforts to understand the combinatorial roles of all clustered Pcdh family members, which also include 14 alpha- and 22 beta-Protocadherins (Pcdhas and Pcdhbs, respectively). We used CRISPR-mediated genome engineering to generate Pcdha/Pcdhg double mutants. Initial analysis shows that their defects are more striking than those of either Pcdha or Pcdhg mutants, suggesting redundancy between these two subclusters.Publication Protocadherins Mediate Dendritic Self-Avoidance in the Mammalian Nervous System(Nature, 2012) Lefebvre, Julie L.; Kostadinov, Dimitar Vladimirov; Chen, Weisheng V.; Maniatis, Thomas; Sanes, JoshuaDendritic arbors of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other. By minimizing gaps and overlaps within the arbor, self-avoidance facilitates complete coverage of a neuron’s territory by its neurites. Remarkably, some neurons that display self-avoidance interact freely with other neurons of the same subtype, implying that they discriminate self from non-self. Here, we demonstrate roles for the clustered protocadherins (Pcdhs) in dendritic self-avoidance and self/non-self discrimination. The Pcdh locus encodes ~60 related cadherin-like transmembrane proteins, at least some of which exhibit isoform-specific homophilic adhesion in heterologous cells and are expressed stochastically and combinatorially in single neurons. Deletion of all 22 Pcdhs in the mouse gamma subcluster (Pcdhgs) disrupts self-avoidance of dendrites in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Further genetic analysis of SACs showed that Pcdhgs act cell-autonomously during development, and that replacement of the 22 Pcdhgs with a single isoform restores self-avoidance. Moreover, expression of the same single isoform in all SACs decreases interactions among dendrites of neighboring SACs (heteroneuronal interactions). These results suggest that homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate a repulsive signal that leads to self-avoidance. In this model, heteroneuronal interactions are normally permitted because dendrites seldom encounter a matched set of Pcdhgs unless they emanate from the same soma. In many respects, our results mirror those reported for Dscam1 in Drosophila: this complex gene encodes thousands of recognition molecules that exhibit stochastic expression and isoform-specific interactions, and mediate both self-avoidance and self/non-self discrimination. Thus, although insect Dscams and vertebrate Pcdhs share no sequence homology, they appear to underlie similar strategies for endowing neurons with distinct molecular identities and patterning their arbors.