Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis

Abstract

Neural stem cells (NSCs) generate new granule cells throughout life in the mammalian hippocampus. Canonical Wnt signaling regulates the differentiation of NSCs towards the neuronal lineage. Here we identified the prospero-related homeodomain transcription factor Prox1 as a target of β-catenin–TCF/LEF signaling in vitro and in vivo. Prox1 overexpression enhanced neuronal differentiation whereas shRNA-mediated knockdown of Prox1 impaired the generation of neurons in vitro and within the hippocampal niche. In contrast, Prox1 was not required for survival of adult-generated granule cells after they had matured, suggesting a role for Prox1 in initial granule cell differentiation but not in the maintenance of mature granule cells. The data presented here characterize a molecular pathway from Wnt signaling to a transcriptional target leading to granule cell differentiation within the adult brain and identify a stage-specific function for Prox1 in the process of adult neurogenesis.

Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus

“…Our study found that the neuronal identity of DG cells was bi-potent during the late stages of these extended periods. By contrast, mature granule cells in the adult DG do not alter their identity upon Prox1 depletion, as previously suggested (Karalay et al, 2011). However, our results demonstrate that the loss of Prox1 in mature DG cells results in a mixed pattern of both DG granule cell and CA3 pyramidal cell gene expression.…”

“…Wnt signaling from the cortical hem, a known morphogen of hippocampal development (Lee et al, 2000;Mangale et al, 2008), is likely to play a crucial role in this process. Wnt signaling postmitotically regulates the expression of Prox1 and NeuroD during adult neurogenesis (Kuwabara et al, 2009;Karalay et al, 2011). Likewise, we observed that Prox1 expression depends on Wnt signaling in immature cells migrating towards the DG primordium (T.I., A.M., H.K., H.E.…”

“…Prox1 plays a crucial role in cell fate determination and in cell cycle regulation during the development of the lymphatic vascular system, lens and retina Dyer et al, 2003;Harvey et al, 2005). Recently, knockout (and knockdown) studies of the Prox1 gene have been reported, in which Prox1 was conditionally depleted by using Nestin-Cre; this resulted in the loss of Prox1 from progenitor cells and also throughout their postmitotic progeny, and revealed that Prox1 is essential for the survival of intermediate progenitors and for their descendent neurons in the DG (Lavado et al, 2010;Karalay et al, 2011). However, the roles that Prox1 plays in postmitotic neuronal cells of the DG during development and adulthood remain to be investigated.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Similarly, Prox1 induces the exit of retinal progenitor cells from the cell cycle and promotes horizontal cell differentiation (Dyer et al 2003). Prox1 overexpression resulted in enhanced neuronal differentiation, whereas knockdown of Prox1 impaired the generation of neurons (Karalay et al 2011). Notably, Prospero has been shown to regulate cell cycle progression because loss of Prospero induced aberrant expression of cell cycle genes such as cyclin A (cycA), cyclin E (cycE), and string (srg) and resulted in increased mitotic activity (Li and Vaessin 2000).…”

“…Moreover, regulators of Prox1 have been reported in other types of cells. In colon cancer cells ) and hippocampus cells (Karalay et al 2011), Prox1 is regulated by the Wnt signal through two binding sites of b-catenin/TCF found in the Prox1 enhancer region at 249 kb and 243 kb upstream of the Prox1 start codon, which induce colon cancer progression and neuronal cell differentiation, respectively. Mash1 (Torii et al 1999) and Foxe3 (Medina-Martinez et al 2005) were found to regulate Prox1 expression in the nervous system and lens, respectively.…”