Neurons that produce dopamine as a neurotransmitter constitute a heterogeneous group involved in the control of various behaviors and physiology. In mammals, dopaminergic neurons are found in distinct clusters mainly located in the ventral midbrain and the caudal forebrain [1]. Although much is known about midbrain dopaminergic neurons, development of diencephalic dopaminergic neurons is poorly understood. Here we demonstrate that Orthopedia (Otp) homeodomain protein is essential for the development of specific subsets of diencephalic dopaminergic neurons. Zebrafish embryos lacking Otp activity are devoid of dopaminergic neurons in the hypothalamus and the posterior tuberculum. Similarly, Otp-/- mouse [2, 3] embryos lack diencephalic dopaminergic neurons of the A11 group, which constitutes the diencephalospinal dopaminergic system. In both systems, Otp is expressed in the affected dopaminergic neurons as well as in potential precursor populations, and it might contribute to dopaminergic cell specification and differentiation. In fish, overexpression of Otp can induce ectopic tyrosine hydroxylase and dopamine transporter expression, indicating that Otp can specify aspects of dopaminergic identity. Thus, Otp is one of the few known transcription factors that can determine aspects of the dopaminergic phenotype and the first known factor to control the development of the diencephalospinal dopaminergic system.
In multicellular organisms, the control of genome duplication and cell division must be tightly coordinated. Essential roles of the minichromosome maintenance (MCM) proteins for genome duplication have been well established. However, no genetic model has been available to address the function of MCM proteins in the context of vertebrate organogenesis. Here, we present positional cloning of a zebrafish mcm5 mutation and characterization of its retina phenotype. In the retina, mcm5 expression correlates closely with the pattern of cell proliferation. By the third day of development, mcm5 is down-regulated in differentiated cells but is maintained in regions containing retinal stem cells. We demonstrate that a gradual depletion of maternally derived MCM5 protein leads to a prolonged S phase, cell-cycle-exit failure, apoptosis, and reduction in cell number in mcm5 m850 mutant embryos. Interestingly, by the third day of development, increased apoptosis is detectable only in the retina, tectum, and hindbrain but not in other late-proliferating tissues, suggesting that different tissues may employ distinct cellular programs in responding to the depletion of MCM5.stem cell ͉ cell proliferation ͉ ciliary marginal zone ͉ embryogenesis ͉ development P roper duplication of the genome during the cell cycle is of paramount importance for the life of an organism. In eukaryotes, each replication origin is ''licensed'' to fire once per cell cycle through the cell-cycle-dependent formation and destruction of a prereplication complex (preRC) (1-3). A key component of this preRC is a family of six structurally related proteins, MCM2 through -7, which are evolutionarily conserved in all eukaryotes. The MCM proteins were originally identified as proteins required for minichromosome maintenance in Saccharomyces cerevisiae (4). MCM2 through -7 belong to a distinct subgroup of the large AAAϩ ATPase family (5) and share a conserved central region of Ϸ200 amino acids (MCM box). Biochemical studies in Xenopus have established the role of MCM2 through -7 as replication-licensing factors (6-8). Subsequent studies illustrate that proper orchestration of the functional interactions among MCM2 through -7 proteins and other components of the preRC by cell-cycledependent protein kinases results in initiation of DNA synthesis once every cell cycle (9, 10). The MCM2 through -7 proteins appear to form heterohexamers and play important roles in initiation and elongation during DNA replication (4,11,12). Furthermore, recent evidence supports involvement of MCMs in many other chromosome transactions, including transcription, chromatin remodeling, and genome stability (13). However, in vivo analysis of MCMprotein functions in multicellular organism has been scarce. Here, we report the isolation, positional cloning, and in-depth characterization of a vertebrate mutant in an MCM-family protein. We demonstrate that the zebrafish m850 allele harbors a mutation in the mcm5 gene and exhibits developmental defects in lateproliferating tissues, including the re...
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