Abstract
BackgroundIn addition to its well-known expression in dorsal telencephalic progenitor cells, where it regulates cell proliferation and identity, the transcription factor Pax6 is expressed in some ventral telencephalic cells, including many postmitotic neurons. Its functions in these cells are unknown.ResultsWe generated a new floxed allele of Pax6 and tested the consequences of a highly specific ventral telencephalic depletion of Pax6. We used the Six3A1A2-Cre allele that drives production of Cre recombinase in a specific region of Pax6-expression close to the internal capsule, through which thalamic axons navigate to cerebral cortex. Depletion in this region caused many thalamic axons to take aberrant routes, either failing to turn normally into ventral telencephalon to form the internal capsule or exiting the developing internal capsule ventrally. We tested whether these defects might have resulted from abnormalities of two structural features proposed to guide thalamic axons into and through the developing internal capsule. First, we looked for the early pioneer axons that project from the region of the future internal capsule to the thalamus and are thought to guide thalamocortical axons to the internal capsule: we found that they are present in conditional mutants. Second, we examined the development of the corridor of Islet1-expressing cells that guides thalamic axons through ventral telencephalon and found that it was broader and less dense than normal in conditional mutants. We also examined corticofugal axons that are thought to interact with ascending thalamocortical axons, resulting in each set providing guidance to the other, and found that some are misrouted to lateral telencephalon.ConclusionThese findings indicate that ventral telencephalic Pax6 is important for formation of the Islet1-expressing corridor and the thalamic and cortical axons that grow through it. We suggest that Pax6 might affect thalamic axonal growth indirectly via its effect on the corridor.
Highlights
In addition to its well-known expression in dorsal telencephalic progenitor cells, where it regulates cell proliferation and identity, the transcription factor Pax6 is expressed in some ventral telencephalic cells, including many postmitotic neurons
We found no overlap between the populations of cells expressing Pax6 in the ventral medial ganglionic eminence (MGE) (Figure 6A, B; the population labeled with white arrowheads corresponds to that indicated by the white arrowhead in Figure 2B) and projecting to the thalamus (Figure 6B, yellow arrowheads)
In the conditional knockout (cKO) described here, we found evidence for less extreme versions of these defects: many thalamic axons navigated through the internal capsule, others deviated ventrally towards the hypothalamus (Figure 5B"); some of those that had deviated ventrally towards the hypothalamus later projected laterally into the ventral part of the ventral telencephalon; some axons that did turn into the internal capsule exited it in a ventral direction towards the amygdala (Figure 4E")
Summary
In addition to its well-known expression in dorsal telencephalic progenitor cells, where it regulates cell proliferation and identity, the transcription factor Pax is expressed in some ventral telencephalic cells, including many postmitotic neurons. Its functions in these cells are unknown. Many transcription factors well-known for their functions in early patterning of the developing nervous system have important functions in subsequent regulation of axonal navigation, by influencing the responses of growing axons and/or the deployment of guidance cues [1618]. In mice lacking Pax, thalamic axons fail to navigate correctly in the ventral telencephalon and a normal internal capsule does not form [12,19,20,21]. The mechanism of action of Pax in thalamocortical axonal development is unknown
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