Development Plasticity and Repair Exam 2 Review Wnts and Synaptogenesis 1 Describe the canonical wnt pathway this means from binding of the receptor to activation of disheveled to blocking the destruction complex to activation of gene transcription be sure to name all proteins and identify their role in this pathway In the canonical Wnt pathway Wnt binds to the receptor Frizzled which activates the protein Disheveled Disheveled blocks the action of the destruction complex made up of APC and Gsk3B which by default would phosphorylate beta catenin and target it for degradation When Disheveled blocks this destruction complex beta catenin is able to enter the nucleus and displace the receptor protein and allow gene transcription 2 Describe the wnt pathway in early synaptogenesis and its consequences on the growth cone and axon as it begins to form the presynaptic complex Identify how it overlaps with the canonical pathway and how it diverges Again identify all proteins involved and their role in this function This particular Wnt pathway is transcription independent meaning early synaptogenesis doesn t require gene transcription for synapse formation Wnt binds with a Frizzled receptor which activated Disheveled Disheveled again blocks the destruction complex made up of APC and Gsk3B APC by default associates with the plus end of the microtubule and promotes axon growth and microtubule recruitment Gsk3B by default also phosphorylates MAP1B When the destruction complex is blocked APC cannot associate with the plus end of microtubules resulting in destabilization and plus end microtubule loss and Gsk3B cannot phosphorylate MAP1B MAP1B when not phosphorylated has the ability to associate with the microtubules and the microtubules loop as a response and form the start of the presynaptic bouton and capture of synaptic associated proteins 3 Describe the wnt pathway in early synaptogenesis and its consequences on the post synaptic side Again describe how this pathway overlaps and how it differs from the canonical pathway all the proteins involved and what functions those proteins serve Once the presynaptic side has been set up it releases Wnt back to the postsynaptic side which has different receptors that allow different synaptic associated proteins to be recruited at the postsynaptic side These lay the way for the more prominent formation of dendritic spines One of the most important proteins recruited is PSD 95 by Wnt7a which is a MAGUK or scaffolding protein that holds the synapse in place 4 Describe the assembly of the postsynaptic density and how it results from pre post synaptic wnt signaling Include the specific forms of wnt involved in excitatory synaptic formation what proteins they activate their roles and what proteins are recruited to the density as well as what their roles are The postsynaptic density is assembled when Wnt from the presynaptic side and bind with the Wnt7a receptors to recruit PSD 95 to the postsynaptic excitatory terminal This MAGUK works as a scaffolding protein that also recruits synaptic associated proteins Wnt5a and 7a can be activated together and with the help of JNK cluster PSD 95 to the excitatory synapse 5 Put it all together Describe the process of synaptogenesis beginning with axon extension into the target zone through the remodeling of both pre and post synaptic sides through the recruitment of synaptic proteins both pre and post synaptic to the formation of functional synapses Be sure to identify all relevant signal molecules all relevant morphological changes all relevant kinases and second messengers all relevant structural and functional proteins in the maturing synapse Once the axon extends into the target zone Wnts signal for the growth cone to collapse from the postsynaptic side The Wnt binds to Frizzled which activates disheveled blocking the destruction complex made up of APC and Gsk3B By default APC associates with the plus end f microtubules promoting axon growth and recruiting microtubules and Gsk3B phosphorylates MAP1B to prevent it from associating with the microtubules When Disheveled blocks this complex APC does not associate with microtubules and Gsk3B does not phosphorylate MAP1B Instead MAP1B is allowed to associate with the microtubules and loops begin to form the presynaptic bouton and clustering of synaptic associated proteins After the presynaptic terminal has been formed it releases Wnt to the postsynaptic side to bind with Wnt receptors When activated Wnt receptors Wnt5a and 7a signal for PSD 95 to be recruited with JNK to the postsynaptic terminal Wnt7a alone can also signal for PSD 95 PSD 95 is a MAGUK that is a scaffolding protein that holds the synapse in place and also recruits synaptic associated proteins to form the postsynaptic density of excitatory synapses 6 Wnts are important for synaptogenesis in development do they play a role in synaptic maintenance loss How do we know They do play a role in maintenance and loss We know this because a constant flow of Wnt allows for the synapses to stay intact However when Dkk1 causes a blockade of Wnt there is a destabilization of the synapse and eventually prolonged Wnt blockade means a complete loss of the synapse 7 Early signaling for synaptogenesis by wnts is independent of transcription how do we know this We know this because blocking ribosomes from associating with mRNA doesn t prevent synaptogenesis Also a time course analysis shows presynaptic formation within 15 minutes of Wnt reception 8 Dendritic spines take on a number of morphologies what are they and what potential role might they play in synaptogenesis plasticity There are four shapes of dendritic spines filopodium stubby thin and mushroom Filopodium and stubby are less stable formations of dendritic spines and are transient structures Thin and mushroom dendritic spine shapes are more stabilized These different morphologies indicate that there can be dendritic spine growth or loss throughout adulthood 9 What is a dendritic spine and what functional role do they play Dendritic spines are protuberances that cover dendrites that contain postsynaptic densities that are often a target of excitatory input It is hypothesized that they are essential for memory They connect axons to dendrites shape membrane potential in response to input and determine dynamics of secondary messengers 10 Where do excitatory synapses tend to form Inhibitory Excitatory synapses form on dendritic spines and inhibitory synapses form on