
GATA6는 WNT 및 BMP 신호 경로를 조절하여 인간 심장 발생 초기 단계에서 전심근 중배엽 패턴화에 필수적이다.


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Haploinsufficiency for GATA6 is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hours of cardiac differentiation is sufficient to partially rescue CPC and CM defects in GATA6 heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by human GATA6 mutations.

### Competing Interest Statement

The authors have declared no competing interest.

GATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis

gata6-조절-wnt-및-bmp-프로그램이-인간-심장-발생-초기-단계에서-전심근-중배엽을-패턴화한다


GATA6 조절 WNT 및 BMP 프로그램이 인간 심장 발생 초기 단계에서 전심근 중배엽을 패턴화한다


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HSPA2는 마우스 배아의 2세포기에 비대칭적으로 발현되며, HSPA2 발현 감소는 내세포괴(ICM) 세포 운명 결정을 저해한다.


The first cell-fate decision is the process by which cells of an embryo take on distinct lineage identities for the first time, thus representing the beginning of developmental patterning. Here, we demonstrate that the molecular chaperone heat shock protein A2 (HSPA2), a member of the 70 kDa heat shock protein (HSP70) family, is asymmetrically expressed in the late 2-cell stage of mouse embryos. The knockdown of Hspa2 in one of the two-cell blastomeres prevented its progeny predominantly toward the inner cell mass (ICM) fate, thus indicating that the differential distribution of HSPA2 in the blastomeres of two-cell embryos can influence the selection of embryonic cell lineages. In contrast, the overexpression of Hspa2 in one of the two-cell blastomeres did not induce blastomeres to differentiate towards the ICM fate. Furthermore, we demonstrated that HSPA2 forms a complex with CARM1 and activates ICM-specific gene expression. Collectively, our results identify HSPA2 as a critical regulator of the first cell-fate decision which specifies the ICM via the execution of commitment and differentiation phases.

### Competing Interest Statement

The authors have declared no competing interest.

The asymmetric expression of HSPA2 in blastomeres governs the first embryonic cell-fate decision

마우스-배아의-첫-번째-세포-운명-결정에-hspa2의-비대칭적-발현이-중요한-역할을-한다


마우스 배아의 첫 번째 세포 운명 결정에 HSPA2의 비대칭적 발현이 중요한 역할을 한다



GATA6 は前心臓中胚葉パターニングの初期段階で WNT および BMP シグナル経路を制御することで、心臓前駆細胞の発生と心筋細胞の分化に重要な役割を果たす。


ヒト初期心臓形成過程における-gata6-の役割-wnt-および-bmp-シグナル経路の制御を通じた前心臓中胚葉パターニングの調節


ヒト初期心臓形成過程における GATA6 の役割 - WNT および BMP シグナル経路の制御を通じた前心臓中胚葉パターニングの調節



The molecular chaperone HSPA2 exhibits asymmetric expression in late 2-cell and 4-cell stage mouse embryos, and its differential distribution governs the first cell-fate decision by regulating ICM-specific gene expression through interaction with CARM1.


the-asymmetric-expression-of-heat-shock-protein-a2-hspa2-regulates-the-first-cell-fate-decision-in-mouse-embryos


The Asymmetric Expression of Heat Shock Protein A2 (HSPA2) Regulates the First Cell-Fate Decision in Mouse Embryos



GATA6 is required for proper patterning of lateral and cardiac mesoderm during the earliest stages of human cardiogenesis, regulating the expression of genes involved in WNT and BMP signaling pathways.


gata6-regulates-early-mesoderm-patterning-and-cardiac-progenitor-cell-specification-in-human-cardiogenesis


GATA6 Regulates Early Mesoderm Patterning and Cardiac Progenitor Cell Specification in Human Cardiogenesis



Necrosis-induced caspase activation in cells distant from the injury site (NiA) promotes regenerative proliferation in the Drosophila wing disc through a novel non-apoptotic function of the initiator caspase Dronc, independent of established Apoptosis-induced Proliferation (AiP) mechanisms.


Tissue necrosis is a devastating complication for many human diseases and injuries. Unfortunately, our understanding of necrosis and how it impacts surrounding healthy tissue – an essential consideration when developing methods to treat such injuries – has been limited by a lack of robust genetically tractable models. Our lab previously established a method to study necrosis-induced regeneration in the Drosophila wing imaginal disc, which revealed a unique phenomenon whereby cells at a distance from the injury upregulate caspase activity in a process called Necrosis-induced Apoptosis (NiA) that is vital for regeneration. Here we have further investigated this phenomenon, showing that NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge. Furthermore, we find that a proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration. This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism. These data reveal a new means by which non-apoptotic Dronc signaling promotes regenerative proliferation in response to necrotic damage.

### Competing Interest Statement

The authors have declared no competing interest.

Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity

necrosis-induced-caspase-activation-promotes-regenerative-proliferation-in-drosophila-wing-discs


Necrosis-Induced Caspase Activation Promotes Regenerative Proliferation in Drosophila Wing Discs



Blastomeres in the mouse embryo polarize asynchronously, with some cells polarizing earlier than others, and this timing of polarization influences their subsequent cell fate specification.


The first lineage allocation in mouse and human embryos separates the inner cell mass (ICM) from the outer trophectoderm (TE). This symmetry breaking event is executed through polarization of cells at the 8-cell stage and subsequent asymmetric divisions, generating polar (TE) and apolar (ICM) cells. Here, we show that embryo polarization is unexpectedly asynchronous. Cells polarizing at the early and late 8-cell stage have distinct molecular and morphological properties that direct their following lineage specification, with early polarizing cells being biased towards producing the TE lineage. More recent studies have also implicated heterogeneities between cells prior to the 8-cell stage in the first lineage allocation: cells exhibiting reduced methyltransferase CARM1 activity at the 4-cell stage are predisposed towards the TE fate. Here, we demonstrate that reduced CARM1 activity and upregulation of its substrate BAF155 promote early polarization and TE specification. These findings provide a link between asymmetries at the 4-cell stage and polarization at the 8-cell stage, mechanisms of the first lineage allocation that had been considered separate.

### Competing Interest Statement

The authors have declared no competing interest.

Asynchronous mouse embryo polarization leads to heterogeneity in cell fate specification

asynchronous-polarization-in-mouse-embryos-leads-to-heterogeneity-in-cell-fate-specification


Asynchronous Polarization in Mouse Embryos Leads to Heterogeneity in Cell Fate Specification



지방체 유래 사이토카인 Upd2는 JAK/STAT 신호전달을 통해 기관지 줄기세포의 규율된 이동을 유지한다.


Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the FGF mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. Here we show that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. We identify the fat body-derived cytokine, Upd2, in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. We show that JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. We provide evidence that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes.

### Competing Interest Statement

The authors have declared no competing interest.

Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells in Drosophila

지방체-유래-사이토카인-upd2가-초파리-기관지-줄기세포의-규율된-이동을-조절한다


지방체 유래 사이토카인 Upd2가 초파리 기관지 줄기세포의 규율된 이동을 조절한다



dact1과 dact2는 Wnt 신호 전달 경로를 조절하여 수렴 신장과 두개안면 발달에 중요한 역할을 한다.


Wnt signaling plays crucial roles in embryonic patterning including the regulation of convergent extension during gastrulation, the establishment of the dorsal axis, and later, craniofacial morphogenesis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled. However, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that dact1 and dact2 genes have dynamic spatiotemporal expression domains that are reciprocal to one another suggesting distinct functions during zebrafish embryogenesis. Both dact1 and dact2 contribute to axis extension, with compound mutants exhibiting a similar convergent extension defect and craniofacial phenotype to the wnt11f2 mutant. Utilizing single-cell RNAseq and an established noncanonical Wnt pathway mutant with a shortened axis (gpc4), we identified dact1/2 specific roles during early development. Comparative whole transcriptome analysis between wildtype and gpc4 and wildtype and dact1/2 compound mutants revealed a novel role for dact1/2 in regulating the mRNA expression of the classical calpain capn8. Over-expression of capn8 phenocopies dact1/2 craniofacial dysmorphology. These results identify a previously unappreciated role of capn8 and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of dact1 and dact2 in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.

### Competing Interest Statement

The authors have declared no competing interest.

Genetic requirement of dact1/2 to regulate noncanonical Wnt signaling and calpain 8 during embryonic convergent extension and craniofacial morphogenesis

dact1-2가-비정형-wnt-신호-전달과-calpain-8-발현을-수정하여-수렴-신장과-두개안면-발달을-조절한다


dact1/2가 비정형 Wnt 신호 전달과 calpain 8 발현을 수정하여 수렴 신장과 두개안면 발달을 조절한다



HvNotch 在水螅頭部再生過程中扮演著協調兩個獨立模式形成系統的角色，其中涉及通過側抑制過程限制觸手系統的形成。


Wnt- and Notch signaling pathways are involved in regulating Hydra head regeneration. The Notch-inhibitor DAPT blocks expression of transcriptional repressor genes including CnGsc and HyHes and attenuates hypostomal HyWnt3 - and HyBMP2/4 expression in regenerating Hydra heads while increasing expression of HyBMP5/8b and the c-fos-related gene HyKayak . Inhibition of the transcriptional activity of β-catenin blocks expression of HyAlx during Hydra head regeneration and prevents formation of tentacles, however hypostome regeneration and Wnt3 expression patterns remain intact. This indicates competing pathways for hypostome and tentacle regeneration. We tested this hypothesis on fresh water polyps of Craspedacusta, which do not have tentacles and thus after head removal only regenerate a hypostome with a crescent of nematocytes around the mouth opening. We found that head regeneration in Craspedacusta was inhibited by the β-catenin-inhibitor iCRT14, but not by the Notch-inhibitor DAPT, indirectly confirming that in Hydra Notch-signaling maybe needed to balance separate signaling modules for hypostome and tentacle formation, involving Wnt3/BMP2/4 or HyAlx/HyBMP5/8b expression, respectively. We suggest that during head regeneration, Notch works by inhibiting HyBMP5/8b expression and HyKayak mediated repression of HyWnt3 , rather than directly activating transcription at the HyWnt3 promoter . We thus conclude that HvNotch mediates between two pattern forming systems in Hydra by coordinating a lateral inhibition process restricting the tentacle system.

### Competing Interest Statement

The authors have declared no competing interest.

HvNotch coordinates two independent pattern forming systems during head regeneration in Hydra by supporting a lateral inhibition process restricting the tentacle system

在水螅頭部再生過程中-hvnotch-協調兩個獨立的模式形成系統-通過支持一個限制觸手系統的側抑制過程


在水螅頭部再生過程中，HvNotch 協調兩個獨立的模式形成系統，通過支持一個限制觸手系統的側抑制過程
