18 research outputs found
The master sex-determination locus in threespine sticklebacks is on a nascent Y chromosome.
BACKGROUND: Many different environmental and genetic sex-determination mechanisms are found in nature. Closely related species can use different master sex-determination switches, suggesting that these developmental pathways can evolve very rapidly. Previous cytological studies suggest that recently diverged species of stickleback fish have different sex chromosome complements. Here, we investigate the genetic and chromosomal mechanisms that underlie sex determination in the threespine stickleback (Gasterosteus aculeatus). RESULTS: Genome-wide linkage mapping identifies a single chromosome region at the distal end of linkage group (LG) 19, which controls male or female sexual development in threespine sticklebacks. Although sex chromosomes are not cytogenetically visible in this species, several lines of evidence suggest that LG 19 is an evolving sex chromosome system, similar to the XX female/XY male system in many other species: (1) males are consistently heterozygous for unique alleles in this region; (2) recombination between loci linked to the sex-determination region is reduced in male meiosis relative to female meiosis; (3) sequence analysis of X- and Y-specific bacterial artificial chromosome (BAC) clones from the sex-determination region reveals many sequence differences between the X- and Y-specific clones; and (4) the Y chromosome has accumulated transposable elements and local duplications. CONCLUSIONS: Taken together, our data suggest that threespine sticklebacks have a simple chromosomal mechanism for sex determination based on a nascent Y chromosome that is less than 10 million years old. Further analysis of the stickleback system will provide an exciting window into the evolution of sex-determination pathways and sex chromosomes in vertebrates
The Mammalian Doublesex Homolog DMRT1 Is a Transcriptional Gatekeeper that Controls the Mitosis versus Meiosis Decision in Male Germ Cells
The switch from mitosis to meiosis is a unique feature of germ cell development. In mammals, meiotic initiation requires retinoic acid (RA), which activates meiotic inducers, including Stra8, but how the switch to meiosis is controlled in male germ cells (spermatogonia) remains poorly understood. Here we examine the role of the Doublesex-related transcription factor DMRT1 in adult spermatogenesis using conditional gene targeting in the mouse. Loss of Dmrt1 causes spermatogonia to precociously exit the spermatogonial program and enter meiosis. Therefore, DMRT1 determines whether male germ cells undergo mitosis and spermatogonial differentiation or meiosis. Loss of Dmrt1 in spermatogonia also disrupts cyclical gene expression in Sertoli cells. DMRT1 acts in spermatogonia to restrict RA responsiveness, directly repress Stra8 transcription, and activate transcription of the spermatogonial differentiation factor Sohlh1, thereby preventing meiosis and promoting spermatogonial development. By coordinating spermatogonial development and mitotic amplification with meiosis, DMRT1 allows abundant, continuous production of sperm.
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â–ş Loss of Dmrt1 causes spermatogonia to precociously enter meiosis â–ş DMRT1 restricts retinoic acid responsiveness and directly represses Stra8 â–ş DMRT1 promotes spermatogonial differentiation â–ş DMRT1 coordinates mitotis and meiosis to allow abundant spermatogenesi
Dmrt5 is controlled by negative autoregulation and has autonomous effects on hippocampus development and neocortex arealization
Patterning of the cerebral hemispheres and arealization of the neocortex depends initially on interplay between morphogens secreted by organizing centers and transcription factors expressed in gradients across the cortical primordium. One of these, Dmrt5/Dmrta2, a zinc finger doublesex and mab-3 related (Dmrt) gene, is expressed in mouse cortical progenitors in a high caudomedial to low rostrolateral gradient. Dmrt5 is required for the development of the caudomedial part of the cerebral cortex but its mode of action remains unclear. In Dmrt5 null mice, the caudomedial cortical organizing center, the Wnt-and Bmp rich cortical hem, is greatly reduced, implying that hem formation relies on DMRT5 activity, and that loss of Dmrt5 affects caudomedial cortex via decreased hem signalling. In a positive feedback loop however, WNT signalling upregulates Dmrt5 expression, suggesting a downstream patterning role for DMRT5. Here we investigated the latter role by inactivating Dmrt5 conditionally in dorsal telencephalon progenitors, and by generating conditional Dmrt5 gain-of-function transgenic mice. In each mouse line, WNT and BMP signaling at the hem appeared largely unaffected. In these conditional mutants, the hemispheres were however smaller than in controls, and the hippocampus and primary visual area (V1) of the neocortex were sharply reduced. No such defects were observed in Dmrt5 hem specific ablated mice. While heterozygous Dmrt5 null mice show a similar reduction of V1 area, opposite changes are observed when Dmrt5 was overexpressed from midgestation onwards. In each mouse line, expression levels of the cortical patterning genes Emx2, Lhx2, and Pax6 were altered. Dmrt5 expression itself was perturbed revealing that it is controlled by negative feedback autoregulation. Together, our findings reveal that DMRT5 levels are tightly controlled and have autonomous effects on hippocampal development and neocortical arealization.info:eu-repo/semantics/inPres
DMRT5 together with DMRT3 directly controls hippocampus development and neocortical area map formation
Mice that are constitutively null for the zinc finger doublesex and mab-3 related (Dmrt) gene, Dmrt5/Dmrta2, show a variety of patterning abnormalities in the cerebral cortex, including the loss of the cortical hem, a powerful cortical signaling center. In conditional Dmrt5 gain of function and loss of function mouse models, we generated bidirectional changes in the neocortical area map without affecting the hem. Analysis indicated that DMRT5, independent of the hem, directs the rostral-to-caudal pattern of the neocortical area map. Thus, DMRT5 joins a small number of transcription factors shown to control directly area size and position in the neocortex. Dmrt5 deletion after hem formation also reduced hippocampal size and shifted the position of the neocortical/paleocortical boundary. Dmrt3, like Dmrt5, is expressed in a gradient across the cortical primordium. Mice lacking Dmrt3 show cortical patterning defects akin to but milder than those in Dmrt5 mutants, perhaps in part because Dmrt5 expression increases in the absence of Dmrt3 DMRT5 upregulates Dmrt3 expression and negatively regulates its own expression, which may stabilize the level of DMRT5. Together, our findings indicate that finely tuned levels of DMRT5, together with DMRT3, regulate patterning of the cerebral cortex
DMRT1 prevents female reprogramming in the postnatal mammalian testis
Sex in mammals is determined in the foetal gonad by the presence or absence of the Y chromosome gene
Sry
, which controls whether bipotential precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells
1
. This pivotal decision in a single gonadal cell type ultimately controls sexual differentiation throughout the body. Sex determination can be viewed as a battle for primacy in the foetal gonad between a male regulatory gene network in which
Sry
activates
Sox9
and a female network involving Wnt/β-catenin signaling (
Supplemental Fig. 1
)
2
. In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogramme granulosa cells into Sertoli cells
2
. Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor
3
in mouse Sertoli cells, even in adults, activates
Foxl2
and reprogrammes Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced, and germ cells appear feminized. Thus
Dmrt1
is essential to maintain mammalian testis determination, and competing regulatory networks maintain gonadal sex long after the foetal choice between male and female.
Dmrt1
and
Foxl2
are conserved throughout vertebrates
4
,
5
and
Dmrt1
-related sexual regulators are conserved throughout metazoans
3
. Antagonism between
Dmrt1
and
Foxl2
for control of gonadal sex may therefore extend beyond mammals. Reprogramming due to loss of
Dmrt1
also may help explain the etiology of human syndromes linked to
DMRT1
, including disorders of sexual differentiation
6
and testicular cancer
7
The Mammalian Doublesex Homolog DMRT1 Is a Transcriptional Gatekeeper that Controls the Mitosis versus Meiosis Decision in Male Germ Cells
SummaryThe switch from mitosis to meiosis is a unique feature of germ cell development. In mammals, meiotic initiation requires retinoic acid (RA), which activates meiotic inducers, including Stra8, but how the switch to meiosis is controlled in male germ cells (spermatogonia) remains poorly understood. Here we examine the role of the Doublesex-related transcription factor DMRT1 in adult spermatogenesis using conditional gene targeting in the mouse. Loss of Dmrt1 causes spermatogonia to precociously exit the spermatogonial program and enter meiosis. Therefore, DMRT1 determines whether male germ cells undergo mitosis and spermatogonial differentiation or meiosis. Loss of Dmrt1 in spermatogonia also disrupts cyclical gene expression in Sertoli cells. DMRT1 acts in spermatogonia to restrict RA responsiveness, directly repress Stra8 transcription, and activate transcription of the spermatogonial differentiation factor Sohlh1, thereby preventing meiosis and promoting spermatogonial development. By coordinating spermatogonial development and mitotic amplification with meiosis, DMRT1 allows abundant, continuous production of sperm