Pitx3 and its role in mDA development

The development of mDA neurons follows a number of stages marked by distinct events. After preparation of the region by signals that provide induction and patterning, cascades of transcription factors involved in specification and differentiation enroll towards fully matured mDA neurons (Hynes and Rosenthal, 1999). Molecular studies into the developmental pathways of these neurons and analysis of mutant animals defective in mDA development have identified several key transcription factors, including Nurrl, Lmxlb and En1/En2, with a function in specification of transmitter identity, neuronal identity and survival of mDA neurons (Smidt et al., 2004a; Perlmann and Wallen-Mackenzie, 2004; Simon et al., 2004).

The paired-like homeodomain transcription factor Pitx3 is uniquely expressed in the brain in post-mitotic mDA neurons during the late differentiation phase from E11.5 onwards, and its expression is conserved among species including human. Genetic analysis of the Aphakia (ak) mouse mutant revealed deletions in the Pitx3 gene, causing the ablation of Pitx3 expression (Smidt et al., 2004a, b). These Pitx3-deficient (ak) mice display neu-

roanatomical alterations in the mDA system from E12.5 onwards, characterized by the absence of mDA neurons in the SNc, whereas mDA neurons in the VTA and the most lateral tip of the SNc are largely spared (Smidt et al., 2004a, b). As a consequence of the neuronal loss in the SNc, connections to the dorsal striatum are virtually absent resulting in a dramatic decrease of dopamine. Initial behavioural analysis of ak mice revealed inconsistent reports on their motor impairments. Although it was stated that ak mice display the akinetic subtype of PD and motor deficits that are reversed by L-DOPA (van den Munckhof et al., 2003; Hwang et al., 2005), we and others observed no characteristic neurological PD symptoms in ak mice (Hwang et al., 2003; Nunes et al., 2003; Smidt et al., 2004a, b).

The mechanism by which Pitx3 influences specifically the survival of SNc mDA neurons is unknown and intriguing. Post-mitotic mDA neurons start to express Pitx3 at the most ventral position of the developing midbrain after they have migrated ventrally from the neuro-epithelium. Therefore, Pitx3 is not directly involved in the proliferation and/or migration of young mDA neurons, but rather in the terminal differentiation and maintenance. A possible explanation for the selective vulnerability, observed in ak mice may be that Pitx3 is not expressed in all mDA neurons. However, we and others found complete overlap between Pitx3 and tyrosine hydroxylase (TH), the key enzyme in dopamine synthesis (Smidt et al., 2004a, b; Zhao et al., 2004). Thus, although all mDA neurons depend on identical signals for their early specification, the specification of neuronal fate of mDA subsets is probably maintained, in part, by independent regulatory cascades.

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