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- All Subjects: development
- Genre: Doctoral Dissertation
- Creators: Smith, Brian
Description
Specific dendritic morphologies are a hallmark of neuronal identity, circuit assembly, and behaviorally relevant function. Despite the importance of dendrites in brain health and disease, the functional consequences of dendritic shape remain largely unknown. This dissertation addresses two fundamental and interrelated aspects of dendrite neurobiology. First, by utilizing the genetic power of Drosophila melanogaster, these studies assess the developmental mechanisms underlying single neuron morphology, and subsequently investigate the functional and behavioral consequences resulting from developmental irregularity. Significant insights into the molecular mechanisms that contribute to dendrite development come from studies of Down syndrome cell adhesion molecule (Dscam). While these findings have been garnered primarily from sensory neurons whose arbors innervate a two-dimensional plane, it is likely that the principles apply in three-dimensional central neurons that provide the structural substrate for synaptic input and neural circuit formation. As such, this dissertation supports the hypothesis that neuron type impacts the realization of Dscam function. In fact, in Drosophila motoneurons, Dscam serves a previously unknown cell-autonomous function in dendrite growth. Dscam manipulations produced a range of dendritic phenotypes with alteration in branch number and length. Subsequent experiments exploited the dendritic alterations produced by Dscam manipulations in order to correlate dendritic structure with the suggested function of these neurons. These data indicate that basic motoneuron function and behavior are maintained even in the absence of all adult dendrites within the same neuron. By contrast, dendrites are required for adjusting motoneuron responses to specific challenging behavioral requirements. Here, I establish a direct link between dendritic structure and neuronal function at the level of the single cell, thus defining the structural substrates necessary for conferring various aspects of functional motor output. Taken together, information gathered from these studies can inform the quest in deciphering how complex cell morphologies and networks form and are precisely linked to their function.
ContributorsHutchinson, Katie Marie (Author) / Duch, Carsten (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Newfeld, Stuart (Committee member) / Smith, Brian (Committee member) / Orchinik, Miles (Committee member) / Arizona State University (Publisher)
Created2013
Description
Development of the central nervous system is an incredible process that relies on multiple extracellular signaling cues and complex intracellular interactions. Approximately 1500 genes are associated with neurodevelopmental disorders, many of which are linked to a specific biochemical signaling cascade known as Extracellular-Signal Regulated Kinase (ERK1/2). Clearly defined mutations in regulators of the ERK1/2 pathway cause syndromes known as the RASopathies. Symptoms include intellectual disability, developmental delay, cranio-facial and cardiac deficits. Treatments for RASopathies are limited due to an in complete understanding of ERK1/2’s role in brain development. Individuals with Neurofibromatosis Type and Noonan Syndrome, the two most common RASopathies, exhibit aberrant functional and white matter organization in non-invasive imaging studies, however, the contributions of neuronal versus oligodendrocyte deficits to this phenotype are not fully understood. To define the cellular functions of ERK1/2 in motor circuit formation, this body of work focuses on two long-range projection neuron subtypes defined by their neurotransmitter. With genetic mouse models, pathological ERK1/2 in glutamatergic neurons reduces axonal outgrowth, resulting in deficits in activity dependent gene expression and the ability to learn a motor skill task. Restricting pathological ERK1/2 within cortical layer V recapitulates these wiring deficits but not the behavioral learning phenotype. Moreover, it is uncovered that pathological ERK1/2 results in compartmentalized expression pattern of phosphorylated ERK1/2. It is not clear whether ERK1/2 functions are similar in cholinergic neuron populations that mediate attention, memory, and motor control. Basal forebrain cholinergic neuron development relies heavily on NGF-TrKA neurotrophic signaling known to activate ERK1/2. Yet the function of ERK1/2 during cholinergic neuronal specification and differentiation is poorly understood. By selectively deleting ERK1/2 in cholinergic neurons, ERK1/2 is required for activity-dependent maturation of neuromuscular junctions in juvenile mice, but not the establishment of lower motor neuron number. Moreover, ERK1/2 is not required for specification of choline acetyltransferase expressing basal forebrain cholinergic neurons by 14 days of age. However, ERK1/2 may be necessary for BFCN maturation by adulthood. Collectively, these data indicate that glutamatergic neuron-autonomous decreases in long-range axonal outgrowth and modest effects on later stages of cholinergic neuron maintenance may be important aspects of neuropathogenesis in RASopathies.
ContributorsRees, Katherina Pavy (Author) / Newbern, Jason (Thesis advisor) / Olive, Foster (Committee member) / Qiu, Shenfeng (Committee member) / Sattler, Rita (Committee member) / Smith, Brian (Committee member) / Arizona State University (Publisher)
Created2024