Francisco Alvarez (Advisor), Paula Bubulya (Committee Member), Timothy Cope (Committee Member), David Ladle (Committee Member), James Olson (Committee Member)
Doctor of Philosophy (PhD)
Locomotor development is dependent on the maturation of spinal cord circuits controlling motor output, but little is known about the development of the spinal interneurons that control motoneuron activity. This study focused on the development of Renshaw cells (RCs) and Ia inhibitory interneurons (IaINs), which mediate recurrent and reciprocal inhibition, respectively, two basic inhibitory circuits for motorneuron control. Both interneurons originate from the same progenitor pool (p1) giving rise to ventral spinal embryonic interneurons denominated V1. V1-derived interneurons (V1-INs) establish local inhibitory connections with ipsilateral motoneurons and express the transcription factor engrailed-1. This characteristic permitted the generation of transgenic mice that were used in this study to genetically label V1 interneuron lineages from embryo to adult. Adult V1-derived Renshaw cells and IaINs share some similar properties, both being inhibitory and establishing ipsilateral connections; but differ in morphology, location in relation to motor pools, expression of calcium binding proteins (calbindin vs. parvabumin), synaptic connectivity and function. These differences are already present in neonates, therefore the purpose of this study was to determine possible embryonic differentiation mechanisms. Using 5"-bromodeoxyuridine birth-dating we demonstrated that V1-INs can be divided into early and late born groups. The early group quickly upregulates calbindin iv expression and includes the Renshaw cells, which maintain calbindin expression through life. The second group includes many cells that postnatally upregulate parvalbumin, including IaINs. This later born group is characterized by upregulation of the transcription factor FoxP2 as they start to differentiate and is retained up to the first postnatal week in many V1-derived IaINs. In contrast, Renshaw cells express the transcription factor MafB that seems relatively specific to them within the V1-INs. Furthermore, Renshaw cells appear attracted to the ventral root exit region and follow a unique migratory route to become specifically placed at this location. In contrast, other V1 interneurons settle more medially and far from the ventral root exit region. MafB expression is upregulated in Renshaw cells only after they have reached their final position among motor axons. Therefore, the specific migration of Renshaw cells might be responsible for their final differentiation and unique relationship with motor axons in adult.
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