Zebrafish Dmrta2 regulates neurogenesis in the telencephalon

Abstract

Although recent findings showed that some Drosophila doublesex and Caenorhabditis elegans mab-3 related genes are expressed in neural tissues during development, their functions have not been fully elucidated. Here, we isolated a zebrafish mutant, ha2, that shows defects in telencephalic neurogenesis and found that ha2 encodes Doublesex and MAB-3 related transcription factor like family A2 (Dmrta2). dmrta2 expression is restricted to the telencephalon, diencephalon and olfactory placode during somitogenesis. We found that the expression of the proneural gene, neurogenin1, in the posterior and dorsal region of telencephalon (posterior-dorsal telencephalon) is markedly reduced in this mutant at the 14-somite stage without any defects in cell proliferation or cell death. In contrast, the telencephalic expression of her6, a Hes-related gene that is known to encode a negative regulator of neurogenin1, expands dramatically in the ha2 mutant. Based on over-expression experiments and epistatic analyses, we propose that zebrafish Dmrta2 controls neurogenin1 expression by repressing her6 in the posterior-dorsal telencephalon. Furthermore, the expression domains of the telencephalic marker genes, foxg1 and emx3, and the neuronal differentiation gene, neurod, are downregulated in the ha2 posterior-dorsal telencephalon during somitogenesis. These results suggest that Dmrta2 plays important roles in the specification of the posterior-dorsal telencephalic cell fate during somitogenesis.

The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1

“…Loss-of-function mutations in Dmrta2 have been linked with microcephaly in zebrafish, mice, and humans (7,(10)(11)(12)(13); however, the role and mechanism of action of Dmrta2 in the control of NPC maintenance and expansion have remained unknown until now. Recently, conditional Dmrta2 mutant mice (Dmrta2 fl/fl ;Emx1-cre) were created that delete Dmrta2 in cortical progenitors after cortical hem formation without impacting Wnt signaling.…”

“…Another site of expression and function of Dmrta2 has been found in the embryonic brain, however (9,10). Dmrta2 loss of function in zebrafish leads to significant reductions in cortical size, coupled with reduced neuronal numbers (10,11).…”

“…Another site of expression and function of Dmrta2 has been found in the embryonic brain, however (9,10). Dmrta2 loss of function in zebrafish leads to significant reductions in cortical size, coupled with reduced neuronal numbers (10,11). Likewise, a smaller neocortex, particularly the dorsomedial neocortex, has been observed in mice carrying null deletions of Dmrta2 (12)(13)(14).…”

FGF signaling establishes the anterior border of the Ciona neural tube

“…DMRT is homologous to the Drosophila doublesex gene, which, in addition to a role in sex determination, also functions in the development of neurons controlling sex-specific behavior (Rideout et al, 2007;Rideout et al, 2010). In vertebrate embryos, DMRT genes mark anterior neural regions, including the nasal placode and presumptive forebrain (Winkler et al, 2004;Huang et al, 2005;Veith et al, 2006;Wen et al, 2009;Yoshizawa et al, 2011). In Ciona, DMRT is first expressed at the 64-cell stage in the a7.10, a7.9 and a7.13 blastomeres, which are progenitors of the anterior neural plate (a-line, rows III-VI) (Imai et al, 2006;Tresser et al, 2010).…”

The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals

“…In the simple chordate Ciona, Dmrt1, the ortholog of vertebrate Dmrt4-5, is essential for the development of anterior neural plate derivatives (Tresser et al 2010). In zebrafish, a recent analysis of a Dmrt5 (Dmrta2) mutant has revealed that it regulates neurogenesis in the telencephalon (Yoshizawa et al 2011). The role of Dmrt genes in mammalian forebrain development is unknown.…”