Neuronal differentiation

sympathetic neurons, suggesting the important role of MASH1 in sympathetic differentiation (Guillemot et al. 1993). MASH1 is transiently induced during neural development to promote neuronal cell differentiation; however,high hASH1 expression persists in neuroblastoma tumors and cell lines (Soderholm et al. 1999; Ichimiya et al. 2001). Retinoic acid treatment decreases the expression of hASH1 and induces neu-rite extension (Ichimiya et al. 2001). hASH1 also directly represses the expression of PACE4, a mammalian subtilin-like proprotein convertase that activates TGF-P-related proteins (e.g., BMPs) in neuro blastoma cell lines (Yoshida et al. 2001). The Notch signaling pathway also plays a key role during neuronal development (Axelson 2004). One of the important regulators of hASH1 is a basic HLH protein, HES1 (Fig. 5.3). HES1 is regulated, at least in part, by Notch signaling and is induced at the transcription level. HES1 directly binds to the promoter of hASH1 and inhibits its transcriptional activation. A constitutively active form of Notch could block neurite extension during the induced differentiation of human neurob-lastoma cells, possibly by inhibiting hASH1 through the induction of HES1 (Radtke and Raj 2003).

5.1.1.3 Phox2a and Phox2b

Phox2a and Phox2b are paired-like homeodomain transcription factors with complete conservation in their homeodomain. They are specifically expressed in noradrenergic neurons and activate the tyrosine hy-droxylase and dopamine-P-hydroxylase genes (Schneider et al. 1999; Stanke et al. 1999; Ernberger 2000). While the expression of Phox2a is regulated by MASH1, Phox2b is not (Lo et al. 1999) (Fig. 5.4). The genetic disruption of either Phox2a or Phox2b gene de-monstrated that both genes are essential for the development of autonomic neural crest derivatives (Morin et al. 1997; Pattyn et al. 1999). Interestingly, Trochet et al. (2004) reported that the Phox2b gene was mutated in a family case of neuroblastoma and in a neuroblastoma patient with Hirschsprung's disease.

Id proteins generally function as inhibitors of differentiation and as positive regulators of proliferation in neuronal development (Lavarone and Lasorella 2004). Id is a protein with the helix-loop-helix domain without a basic region and forms heterodimers with bHLH proteins, e.g., MASH1 and HES1 to inhibit their trans-activation function (Massari and Murre 2000). In pedi-atric cancers, MYC oncoproteins and EWS-Ets fusion proteins are targeted to induce Id2 which in turn inhibits Rb and other target proteins including bHLH proteins, Ets and Pax. In neuroblastoma, MYCN has been shown to induce Id2 which stimulates cell proliferation by inhibiting Rb function (Lasorella et al. 2000).

Figure 5.3

Notch signaling transactivates gene expression to induce neuronal differentiation. Binding of the ligand delta to its receptor notch triggers intramembrane proteolytic cleavage by y-secretase. This results in the release of the notch intracellular domain (NICD), which then translocates to the nucleus where it associates with the CSL family of DNA binding proteins and trans-activates gene expression. The target genes include HES1,MATH1,NF-kB,cyclin D1,p21,and neurogenin.HES1 then inhibits transactivation of MASH1 (hASH1)

Figure 5.4

Regulatory network controlling sympathetic neuron development. BMP2 and BMP4 are required for the expression of MASH1 and Phox2b. HES1 induced by notch signaling inhibits expression of MASH1. MASH1 and Phox2b are genetically upstream of Phox2a, and Phox2b is genetically upstream of Gata3. Expression of tyrosine hydroxylase (TH) and dopa-mine-^-hydroxylase (DBH) depends on MASH1, Phox2b, and Gata3. Cyclic AMP also controls expression of TH and DBH. Phox2a and Phox2b may affect induction or maintenance of MASH1 expression. MASH1, Phox2a,and Phox2b regulate the downstream neurogenic program, leading to terminal differentiation of sympathetic neurons by inducing the genes, e.g., Trks, NF160, peripherin,and SCG10

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