Zic2 mutation causes holoprosencephaly via disruption of NODAL signalling.

The ZIC2 transcription factor is one of the genes most commonly mutated in Holoprosencephaly (HPE) probands. Studies in cultured cell lines and mice have shown a loss of ZIC2 function is the pathogenic mechanism but the molecular details of this ZIC2 requirement remain elusive. HPE arises when signals that direct morphological and fate changes in the developing brain and facial primordia are not sent or received. One critical signal is sent from the prechordal plate (PrCP) which develops beneath the ventral forebrain. An intact NODAL signal transduction pathway and functional ZIC2 are both required for PrCP establishment. We now show that ZIC2 acts downstream of the NODAL signal during PrCP development. ZIC2 physically interacts with SMAD2 and SMAD3, the receptor activated proteins that control transcription in a NODAL dependent manner. Together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and Zic2 also controls the foxA2 expression during Xenopus development. Variant forms of the ZIC2 protein, associated with HPE in man or mouse, are deficient in their ability to influence SMAD-dependent transcription. These findings reveal a new mechanism of NODAL signal transduction in the mammalian node and provide the first molecular explanation of how ZIC2 loss-of-function precipitates HPE.

Improving 10-year atherosclerotic cardiovascular disease estimation management using a Smartphrase for automated risk screening.

BACKGROUND: Cardiovascular disease (CVD) is the most common cause of death in the United States, and 90% of cardiovascular events are preventable. The 2020 American College of Cardiology/American Heart Association Guidelines on the Primary Prevention of Cardiovascular Disease recommends 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimates for 40- to 75-year-old adults with CVD risk indications to decrease the likelihood of cardiovascular events. LOCAL PROBLEM: At the project site, the 10-year ASCVD risk estimates were rarely completed by providers. The purpose of this project was to increase 10-year ASCVD risk estimation screening and improve pharmacological therapy for 40- to 75-year-old patients with CVD risk indications. METHODS: To increase 10-year ASCVD risk estimation screening and improve pharmacological therapy, a multifaceted bundle was created for providers. INTERVENTIONS: Three interventions were initiated: an electronic health record Smartphrase was created to produce automatic 10-year risk scores; laminated paper reminders for the Smartphrase were visible on providers' desks; educational in-services were performed to promote risk score adherence. RESULTS: The project aims were achieved with an increase from a 14% completion rate for 10-year ASCVD risk estimation during the preintervention phase to a 98% completion rate at the end of the postintervention phase. Appropriate pharmacological therapy improved from a 64% rate during the preintervention phase to a maximum rate of 79% during postintervention. CONCLUSION: The project was effective at increasing risk estimate completion and improving appropriate pharmacological therapy. There was an increase in provider-patient discussions toward primary prevention for cardiovascular events.

Mouse strains for the ubiquitous or conditional overexpression of the Flii gene.

The gelsolin related actin binding protein, Flii, is able to regulate wound healing; mice with decreased Flii expression show improved wound healing whereas mice with elevated Flii expression exhibit impaired wound healing. In both mice and humans Flii expression increases with age and amelioration of FLII activity represents a possible therapeutic strategy for improved wound healing in humans. Despite analysis of Flii function in a variety of organisms we know little of the molecular mechanisms underlying Flii action. Two new murine alleles of Flii have been produced to drive constitutive or tissue-specific expression of Flii. Each strain is able to rescue the embryonic lethality associated with a Flii null allele and to impair wound healing. These strains provide valuable resources for ongoing investigation of Flii function in a variety of biological processes.

Zic2-associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation.

The putative transcription factor ZIC2 is associated with a defect of forebrain development, known as Holoprosencephaly (HPE), in humans and mouse, yet the mechanism by which aberrant ZIC2 function causes classical HPE is unexplained. The zinc finger domain of all mammalian Zic genes is highly homologous with that of the Gli genes, which are transcriptional mediators of Shh signalling. Mutations in Shh and many other Hh pathway members cause HPE and it has been proposed that Zic2 acts within the Shh pathway to cause HPE. We have investigated the embryological cause of Zic2-associated HPE and the relationship between Zic2 and the Shh pathway using mouse genetics. We show that Zic2 does not interact with Shh to produce HPE. Moreover, molecular defects that are able to account for the HPE phenotype are present in Zic2 mutants before the onset of Shh signalling. Mutation of Zic2 causes HPE via a transient defect in the function of the organizer region at mid-gastrulation which causes an arrest in the development of the prechordal plate (PCP), a structure required for forebrain midline morphogenesis. The analysis provides genetic evidence that Zic2 functions during organizer formation and that the PCP develops via a multi-step process.