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Male sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a "female protective effect" (FPE) envisions males and females have "differing thresholds" under a "liability threshold model" (DT-LTM). Specifically, this model posits that females require either a greater number or larger magnitude of risk factors (i.e., greater liability) to manifest ASD, which is supported by the finding that a greater proportion of females with ASD have highly penetrant genetic mutations. Herein, we derive testable hypotheses from the DT-LTM for ASD, investigating heritability, familial recurrence, correlation between ASD penetrance and sex ratio, population traits, clinical features, the stability of the sex ratio across diagnostic changes, and highlight other key prerequisites. Our findings reveal that several key predictions of the DT-LTM are not supported by current data, requiring us to establish a different conceptual framework for evaluating alternate models that explain sex differences in ASD.

The multizinc finger transcription factor Sall1 is a critical developmental regulator that mediates repression through the recruitment of the nucleosome remodeling and deacetylase (NuRD) complex. Although a short conserved peptide motif in Sall1 is sufficient to recruit NuRD, its ability to regulate native Sall1 target genes in vivo has not been demonstrated. In this report, we demonstrate an in vivo role for the Sall1 repression motif and describe a novel direct target gene of Sall1, Gbx2, that is directly repressed in a NuRD-dependent fashion. The ability of Sall1 to repress Gbx2 was impaired in Xenopus embryos expressing mutant forms of Sall1 that are defective for NuRD binding. Finally, we demonstrate that protein kinase C phosphorylates serine 2 of the Sall1 repression motif and reveal that a phosphomimetic mutation of serine 2 disrupts the ability of Sall1 to repress Gbx2 in cell culture and Xenopus embryos. Together, these studies establish that Sall1 recruits NuRD via the Sall1 repression motif to mediate repression of a native target gene and suggest a model in which dynamic control of gene expression by Sall1 is modulated by serine phosphorylation of the Sall1 repression motif.

The embryo transitions to new cell divisions and the transfer of the maternal control of development to zygotic genome is studied. The analysis shows that a balance of Cyclin-dependent Kinase 1 and Cyclin B (Cdk1-Cyc-B) activity relative to Drosophila checkpoint kinase Chk1 determines these cell diversions.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2005.10.047 Byline: Jennifer J. Taylor (a), Ting Wang (b), Kristen L. Kroll (a) Keywords: Transcription; Geminin; Xenopus; Transgenic; Wnt; BMP; Tcf; Vent; Neural Abstract: Vertebrate neural development has been extensively investigated. However, it is unknown for any vertebrate gene how the onset of neural-specific expression in early gastrula embryos is transcriptionally regulated. geminin expression is among the earliest markers of dorsal, prospective neurectoderm at early gastrulation in Xenopus laevis. Here, we identified two 5' sequence domains that are necessary and sufficient to drive neural-specific expression during gastrulation in transgenic Xenopus embryos. Each domain contained putative binding sites for the transcription factor Tcf, which can mediate Wnt signaling and for Vent homeodomain proteins, transcriptional repressors that mediate BMP signaling. Results from embryos transgenic for constructs with mutated Tcf or Vent sites demonstrated that signaling through the Tcf sites was required for dorsal-specific expression at early gastrulation, while signaling through the Vent sites restricted geminin expression to the prospective neurectoderm at mid-gastrulation. Consistent with these results, geminin 5' regulatory sequences and endogenous Xgem responded positively to Wnt signaling and negatively to BMP signaling. The two 5' sequence domains were also conserved among geminin orthologs. Together, these results demonstrate that signaling through Tcf and Vent binding sites regulates transcription of geminin in prospective neurectoderm during gastrulation. Author Affiliation: (a) Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA (b) Department of Genetics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA Article History: Received 22 August 2005; Revised 12 October 2005; Accepted 14 October 2005

The role of Tcf- and Vent-binding sites in controlling the expression of geminin gene during neural development in Xenopus laevis early embryos is studied.

SWI/SNF chromatin-remodeling protein Brg1 is identified as an interacting partner of Geminin. It is demonstrated that Geminin antagonizes Brg1 activity during neurogenesis to maintain the undifferentiated cell state.