Abstract
The vertebrate hindbrain is transiently divided along the anterior-posterior axis into seven morphologically and molecularly distinct segments, or rhombomeres, that correspond to Hox expression domains. The establishment of a proper 'hox code' is required for the development of unique rhombomere identities, including specification of neuronal fates. valentino (val), the zebrafish ortholog of mafB/Kreisler (Kr), encodes a bZip transcription factor that is required cell autonomously for the development of rhombomere (r) 5 and r6 and for activation of Hox group 3 gene expression. Recent work has demonstrated that the expression of val itself depends on three factors: retinoic acid (RA) signals from the paraxial mesoderm; fibroblast growth factor (Fgf) signals from r4; and variant hepatocyte nuclear factor 1 (vhnf1, also known as tcf2), a homeodomain transcription factor expressed posterior to the r4-5 boundary. We have investigated the interactions between these inputs onto val expression in the developing zebrafish hindbrain. We show that RA induces val expression via activation of vhnf1 expression in the hindbrain. Fgf signals from r4, acting through the MapK pathway, then cooperate with Vhnf1 to activate val expression and subsequent r5 and r6 development. Additionally, vhnf1 and val function as part of a multistep process required for the repression of r4 identity in the posterior hindbrain. vhnf1 acts largely independently of val to repress the r4 'hox code' posterior to the r4-5 boundary and therefore to block acquisition of r4-specific neuronal fates in the posterior hindbrain. However, vhnf1 is not able to repress all aspects of r4 identity equivalently. val is required downstream of vhnf1 to repress r4-like cell-surface properties, as determined by an 'Eph-ephrin code', by repressing ephrin-B2a expression in r5 and r6. The different requirements for vhnf1 and val to repress hoxb1a and ephrin-B2a, respectively, demonstrate that not all aspects of an individual rhombomere's identity are regulated coordinately.
Highlights
The rhombomeres of the vertebrate hindbrain are a series of seven transient segments first distinguished by expression of molecular markers and later as morphological segments giving rise to distinct neuronal fates (Lumsden and Krumlauf, 1996; Moens and Prince, 2002)
The acquisition of proper anteroposterior (AP) identity and subsequent neuronal development in the hindbrain is established by the Hox genes that are expressed in nested, rhombomere-restricted domains and that play a role in the specification of AP axis identities across metazoan phyla (Wilkinson et al, 1989)
This work focuses on the genetic hierarchy that establishes appropriate Hox gene expression in the caudal hindbrain, where specification of rhombomere (r) 5 and r6 identity involves the activation of Hox paralog group 3 expression and the repression of hox1 gene expression
Summary
The rhombomeres of the vertebrate hindbrain are a series of seven transient segments first distinguished by expression of molecular markers and later as morphological segments giving rise to distinct neuronal fates (Lumsden and Krumlauf, 1996; Moens and Prince, 2002). Previous work has shown that the transcription factors MafB and Krox are direct regulators of Hox gene expression in r5 and r6. Kreisler (Kr) and valentino (val), the mouse and zebrafish orthologs of mafB, respectively, are required for normal r5 and r6 development (Cordes and Barsh, 1994; McKay et al, 1994; Moens et al, 1996; Moens et al, 1998; Prince et al, 1998) and MafB has been shown to activate hoxb and hoxa expression directly in transgenic mice (Manzanares et al, 1997; Manzanares et al, 1999a; Manzanares et al, 2001; Manzanares et al, 2002). Hox genes are both necessary and sufficient for the development of somatic motoneurons in the hindbrain (Gaufo et al, 2003; Guidato et al, 2003)
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