Townes-Brocks syndrome (TBS, OMIM #107480) is an autosomal dominant disorder that causes multiple birth defects including renal, ear, anal and limb malformations. Mutations in SALL1 have been postulated to cause TBS by haploinsufficiency; however, a mouse model carrying a sall1-null allele does not mimic the human syndrome. Since the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein. To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS. Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities. Homozygous sall1-DeltaZn2-10 mutant mice exhibit more severe defects than sall1-null mice including complete renal agenesis, exencephaly, limb and anal deformities. We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. These data support a model for the pathogenesis of TBS in which expression of a truncated SALL1 protein causes abnormal development of multiple organs.

No abstract

Male sterility is an essential trait in hybrid seed production for monoclinous crops, including rice and wheat. However, compared with the high percentage of hybrid rice planted in the world, little commercial hybrid wheat is planted globally as a result of the lack of a suitable system for male sterility. Therefore, understanding the molecular nature of male fertility in wheat is critical for commercially viable hybrid wheat. Here, we report the cloning and characterization of () in bread wheat by using a combination of advanced genomic approaches. is a newly evolved gene in the Poaceae that is specifically expressed in microsporocytes, and is essential for microgametogenesis. Orthologs of are expressed in diploid and allotetraploid ancestral species. Orthologs of are epigenetically silenced in the A and D subgenomes of allohexaploid wheat; only from the B subgenome is expressed. The encoded protein, Ms1, is localized to plastid and mitochondrial membranes, where it exhibits phospholipid-binding activity. These findings provide a foundation for the development of commercially viable hybrid wheat.

Light elicits different growth responses in different organs of plants. These organ-specific responses are prominently displayed during de-etiolation. While major light-responsive components and early signaling pathways in this process have been identified, this information has yet to explain how organ-specific light responses are achieved. Here, we report that members of the TEOSINTE BRANCHED1, CYCLOIDEA, and PCF (TCP) transcription factor family participate in photomorphogenesis and facilitate light-induced cotyledon opening in Arabidopsis (Arabidopsis thaliana). Chromatin immunoprecipitation sequencing and RNA sequencing analyses indicated that TCP4 targets a number of SMALL AUXIN UPREGULATED RNA (SAUR) genes that have previously been shown to exhibit organ-specific, light-responsive expression. We demonstrate that TCP4-like transcription factors, which are predominantly expressed in the cotyledons of both light-and dark-grown seedlings, activate SAUR16 and SAUR50 expression in response to light. Light regulates the binding of TCP4 to the promoters of SAUR14, SAUR16, and SAUR50 through PHYTOCHROME-INTERACTING FACTORs (PIFs). PIF3, which accumulates in etiolated seedlings and its levels rapidly decline upon light exposure, also binds to the SAUR16 and SAUR50 promoters, while suppressing the binding of TCP4 to these promoters in the dark. Our study reveals that the interplay between light-responsive factors PIFs and the developmental regulator TCP4 determines the cotyledon-specific light regulation of SAUR16 and SAUR50, which contributes to cotyledon closure and opening before and after de-etiolation.

Summary Ski‐interacting protein (SKIP) is a bifunctional regulator of gene expression that works as a splicing factor as part of the spliceosome and as a transcriptional activator by interacting with EARLY FLOWERING 7 (ELF7). MOS4‐Associated Complex 3A (MAC3A) and MAC3B interact physically and genetically with SKIP, mediate the alternative splicing of c. 50% of the expressed genes in the Arabidopsis genome, and are required for the splicing of a similar set of genes to that of SKIP. SKIP interacts physically and genetically with splicing factors and Polymerase‐Associated Factor 1 complex (Paf1c) components. However, these splicing factors do not interact either physically or genetically with Paf1c components. The SKIP‐spliceosome complex mediates circadian clock function and abiotic stress responses by controlling the alternative splicing of pre‐mRNAs encoded by clock‐ and stress tolerance‐related genes. The SKIP‐Paf1c complex regulates the floral transition by activating FLOWERING LOCUS C (FLC) transcription. Our data reveal that SKIP regulates floral transition and environmental fitness via its incorporation into two distinct complexes that regulate gene expression transcriptionally and post‐transcriptionally, respectively. It will be interesting to discover in future studies whether SKIP is required for integration of environmental fitness and growth by control of the incorporation of SKIP into spliceosome or Paf1c in plants.

The parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-alpha (TGF-alpha). TGF-alpha stimulates growth through activation of its receptor, the epidermal growth factor receptor (EGFR), normally expressed in the parathyroid glands. Because enhanced coexpression of TGF-alpha and EGFR causes aggressive cellular growth, these studies utilized highly specific inhibitors of EGFR tyrosine kinase, a step mandatory for TGF-alpha-induced EGFR activation, to assess the contribution of growth signals from enhanced expression of TGF-alpha exclusively or both TGF-alpha and EGFR to the rapid parathyroid growth induced by kidney disease and exacerbated by high-phosphorus (P) and low-calcium (Ca) diets in rats. The enhancement in parathyroid gland weight and proliferating activity (proliferating cell nuclear antigen/Ki67) induced by kidney disease and aggravated by either high P or low Ca intake, within the first week after 5/6 nephrectomy, in rats, coincided with simultaneous increases (2- to 3-fold) in TGF-alpha and EGFR content. Conversely, prevention of the increases in both TGF-alpha and EGFR paralleled the efficacy of either P restriction or high-Ca intake in ameliorating uremia-induced parathyroid hyperplasia. More importantly, suppression of TGF-alpha/EGFR signaling, through prophylactic administration of potent and highly selective inhibitors of ligand-induced EGFR activation, completely prevented both high-P- and low-Ca-induced parathyroid hyperplasia as well as TGF-alpha self-upregulation. Thus enhanced parathyroid TGF-alpha/EGFR expression, self-upregulation, and growth signals occur early in kidney disease, are aggravated by low-Ca and high-P intake, and constitute the main pathogenic mechanism of the severity of parathyroid hyperplasia.

Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-␣ is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-␣, the progression of growth, and the reduction of VDR. Increased TGF-␣/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-␤, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-␤ transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-␣ activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.

Although it is well established that the Polycomb Group (PcG) complexes maintain gene repression through the incorporation of H2AK121ub and H3K27me3, little is known about the effect of these modifications on chromatin accessibility, which is fundamental to understand PcG function. Here, by integrating chromatin accessibility, histone marks and expression analyses in different Arabidopsis PcG mutants, we show that PcG function regulates chromatin accessibility. We find that H2AK121ub is associated with a less accessible but still permissive chromatin at transcriptional regulation hotspots. Accessibility is further reduced by EMF1 acting in collaboration with PRC2 activity. Consequently, H2AK121ub/H3K27me3 marks are linked to inaccessible although responsive chromatin. In contrast, only-H3K27me3-marked chromatin is less responsive, indicating that H2AK121ub-marked hotspots are required for transcriptional responses. Nevertheless, despite the loss of PcG activities leads to increased chromatin accessibility, this is not necessarily accompanied by transcriptional activation, indicating that accessible chromatin is not always predictive of gene expression.