Abstract
Neurogenesis in the dentate gyrus of the adult hippocampus has been implicated in neural plasticity and memory, but the molecular mechanisms controlling the proliferation and differentiation of newborn neurons and their integration into the synaptic circuitry are still largely unknown. To investigate this issue, we have analyzed the adult hippocampal neurogenesis in a PC3/Tis21-null mouse model. PC3/Tis21 is a transcriptional co-factor endowed with antiproliferative and prodifferentiative properties; indeed, its upregulation in neural progenitors has been shown to induce exit from cell cycle and differentiation. We demonstrate here that the deletion of PC3/Tis21 causes an increased proliferation of progenitor cells in the adult dentate gyrus and an arrest of their terminal differentiation. In fact, in the PC3/Tis21-null hippocampus postmitotic undifferentiated neurons accumulated, while the number of terminally differentiated neurons decreased of 40%. As a result, PC3/Tis21-null mice displayed a deficit of contextual memory. Notably, we observed that PC3/Tis21 can associate to the promoter of Id3, an inhibitor of proneural gene activity, and negatively regulates its expression, indicating that PC3/Tis21 acts upstream of Id3. Our results identify PC3/Tis21 as a gene required in the control of proliferation and terminal differentiation of newborn neurons during adult hippocampal neurogenesis and suggest its involvement in the formation of contextual memories.
Highlights
PC3, known as Tis21 or BTG2, originally isolated as gene induced by nerve growth factor, negatively controls a cell cycle checkpoint at the G1 to S phase transition in fibroblasts and neuronal cells by direct inhibition of the activity of cyclin D1 promoter [3,4,5]
We found that the terminal differentiation of adult-generated hippocampal granule neurons is dependent on PC3/Tis21 expression, being impaired in mice ablated of PC3/Tis21
Precursors Is Arrested before Terminal Differentiation in the Absence of PC3/Tis21 We sought in first place to assess whether the development of hippocampal progenitor cells is dependent on PC3/Tis21 expression
Summary
PC3, known as Tis or BTG2 (in rat, mouse and human, respectively; see for review [1,2]), originally isolated as gene induced by nerve growth factor, negatively controls a cell cycle checkpoint at the G1 to S phase transition in fibroblasts and neuronal cells by direct inhibition of the activity of cyclin D1 promoter [3,4,5]. The expression of PC3/Tis has been detected in the dentate gyrus of adult hippocampus, in type-2 progenitor cells as well as in differentiated neurons [15]. By means of a transgenic mouse over-expressing PC3/Tis in adult hippocampal progenitor cells we have shown that PC3/Tis accelerates their differentiation, without affecting the final number of differentiated neurons. We found that the synaptic plasticity in the dentate gyrus and the performance in different hippocampus-dependent spatial learning and memory tests was severely reduced. This suggested that the time the young neurons spend in different states of neuronal differentiation is critical for their ultimate function in learning and memory [16]
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