Prospero-related homeobox 1 (Prox1) at the crossroads of diverse pathways during adult neural fate specification

Abstract

Over the last decades, adult neurogenesis in the central nervous system (CNS) has emerged as a fundamental process underlying physiology and disease. Recent evidence indicates that the homeobox transcription factor Prox1 is a critical intrinsic regulator of neurogenesis in the embryonic CNS and adult dentate gyrus (DG) of the hippocampus, acting in multiple ways and instructed by extrinsic cues and intrinsic factors. In the embryonic CNS, Prox1 is mechanistically involved in the regulation of proliferation vs. differentiation decisions of neural stem cells (NSCs), promoting cell cycle exit and neuronal differentiation, while inhibiting astrogliogenesis. During the complex differentiation events in adult hippocampal neurogenesis, Prox1 is required for maintenance of intermediate progenitors (IPs), differentiation and maturation of glutamatergic interneurons, as well as specification of DG cell identity over CA3 pyramidal fate. The mechanism by which Prox1 exerts multiple functions involves distinct signaling pathways currently not fully highlighted. In this mini-review, we thoroughly discuss the Prox1-dependent phenotypes and molecular pathways in adult neurogenesis in relation to different upstream signaling cues and cell fate determinants. In addition, we discuss the possibility that Prox1 may act as a cross-talk point between diverse signaling cascades to achieve specific outcomes during adult neurogenesis.

Keywords: Prox1; adult neurogenesis; dentate gyrus; hippocampus; neural differentiation; neuronal progenitors; nuclear receptors.

Figure 1

Schematic depiction of the involvement of Prox1 in diverse critical pathways that regulate neurogenesis during adult and embryonic NSC fate specification. Prox1 may act as a key cross-talk point between upstream and downstream signaling processes to achieve specific outcomes during neurogenesis in the adult DG of the hippocampus (i.e., canonical Wnt, miR-181α; continuous line) and the embryonic CNS (i.e., Notch1, Mash1/Ngn2 proneural genes, Sox1, Stau2, Olig2; discontinuous line). Furthermore, Prox1 acts as tumor suppressor gene in neuroblastoma cells by regulating basic components of the cell cycle machinery (i.e., p27-Kip1, Cdc25A) (see also Table 1).