Phenotypic Specification of Striatal Progenitors; Evidence for both cell-autonomous and environmental control as studied by transplantation into the adult and developing rodent brain

Sammanfattning: The striatum is the major component of the ventral telencephalon and basal ganglia, involved in the processing of cortical information. The vast majority of the neuronal population in the striatum are striatal projection neurons, with connection to the globus pallidus and substantia nigra. The remaining striatal population consists largely of cholinergic, parvalbumin or somatostatin-containing interneurons. The striatum is thought to develop from two transient elevations arising in the ventral telencephalon at midgestation, the lateral and medial ganglionic eminence. The studies in this thesis are aimed at localizing the specific progenitors for striatal neuronal subtypes and identifying the developmental mechanisms utilized by the embryonic brain for proper differentiation of these distinct neurons. These questions were addressed by transplanting neural progenitors into brains, ranging from adult to early embryonic stages. Striatal projection neurons were observed to be generated predominantly from progenitors in the lateral ganglionic eminence. Progenitors in this structure were also found to generate somatostatin neurons. In contrast, cholinergic and ventral telencephalic parvalbumin-containing neurons were found to be generated from the early stage medial ganglionic eminence. In addition, thyroid transcription factor-1 was observed to define the early stage medial ganglionic eminence and this protein was also detected in cholinergic and parvalbumin expressing cells from early differentiation till adulthood. Progenitors differentiating into distinct neuronal subtypes were found to be specified at an early stage in the generation of the distinct subtypes, respectively. These progenitors displayed specification in terms of neurochemical expression, axonal outgrowth and migration. This specification appeared to be cell-autonomous and maintained through a number of cell divisions since heterotopic transplantation into both the adult and neonatal brain environment was unable to alter their specified fate. However, environmental signaling could respecify many ventral telencephalic progenitors following heterotopic transplantation into the embryonic brain, thus revealing a broad developmental potential of this population. These results demonstrate that specific progenitors within the lateral and medial ganglionic eminences contribute to distinct neuronal subtypes. These progenitors are specified early by cell-autonomous mechanisms which direct differentiation into distinct neuronal identities. However, these neural progenitors can be respecified under the influence of environmental signaling present in the neurogenic embryonic brain. Thus, cell fate determination during ventral telencephalic development appears to invlove both cell-autonomous and local inductive mechanisms.