Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disorder resulting from germline mutations in the NF2 gene. Bilateral vestibular schwannomas, tumors on cranial nerve VIII, are pathognomonic for NF2 disease. Furthermore, schwannomas also commonly develop in other cranial nerves, dorsal root ganglia and peripheral nerves. These tumors are a major cause of morbidity and mortality, and medical therapies to treat them are limited. Animal models that accurately recapitulate the full anatomical spectrum of human NF2-related schwannomas, including the characteristic functional deficits in hearing and balance associated with cranial nerve VIII tumors, would allow systematic evaluation of experimental therapeutics prior to clinical use. Here, we present a genetically engineered NF2 mouse model generated through excision of the Nf2 gene driven by Cre expression under control of a tissue-restricted 3.9kbPeriostin promoter element. By 10 months of age, 100% of Postn-Cre; Nf2(flox/flox) mice develop spinal, peripheral and cranial nerve tumors histologically identical to human schwannomas. In addition, the development of cranial nerve VIII tumors correlates with functional impairments in hearing and balance, as measured by auditory brainstem response and vestibular testing. Overall, the Postn-Cre; Nf2(flox/flox) tumor model provides a novel tool for future mechanistic and therapeutic studies of NF2-associated schwannomas.

Cardiac fibroblasts are the most abundant cell in the mammalian heart. While they have been historically underappreciated in terms of their functional contributions to cardiac development and physiology, they and their activated form, myofibroblasts, are now known to play key roles in both development and disease through structural, paracrine, and electrical interactions with cardiomyocytes. The lack of specific markers for fibroblasts currently convolutes the study of this dynamic cell lineage, but advances in marker analysis and lineage mapping technologies are continuously being made. Understanding how to best utilize these tools, both individually and in combination, will help to elucidate the functional significance of fibroblast-cardiomyocyte interactions in vivo. Here we review what is currently known about the diverse roles played by cardiac fibroblasts and myofibroblasts throughout development and periods of injury with the intent of emphasizing the duality of their nature.

The mature outflow tract (OFT) is, in basic terms, a short conduit. It is a simple, although vital, connection situated between contracting muscular heart chambers and a vast embryonic vascular network. Unfortunately, it is also a focal point underlying many multifactorial congenital heart defects (CHDs). Through the use of various animal models combined with human genetic investigations, we are beginning to comprehend the molecular and cellular framework that controls OFT morphogenesis. Clear roles of neural crest cells (NCC) and second heart field (SHF) derivatives have been established during OFT formation and remodeling. The challenge now is to determine how the SHF and cardiac NCC interact, the complex reciprocal signaling that appears to be occurring at various stages of OFT morphogenesis, and finally how endocardial progenitors and primary heart field (PHF) communicate with both these colonizing extra-cardiac lineages. Although we are beginning to understand that this dance of progenitor populations is wonderfully intricate, the underlying pathogenesis and the spatiotemporal cell lineage interactions remain to be fully elucidated. What is now clear is that OFT alignment and septation are independent processes, invested via separate SHF and cardiac neural crest (CNC) lineages. This review will focus on our current understanding of the respective contributions of the SHF and CNC lineage during OFT development and pathogenesis.

Cardiac fibroblasts are the most abundant cell in the mammalian heart. While they have been historically overlooked in terms of functional contributions to development and physiology, cardiac fibroblasts are now front and center. They are currently recognized as key protagonists during both normal development and cardiomyopathy disease, and work together with cardiomyocytes through paracrine, structural, and potentially electrical interactions. However, the lack of specific biomarkers and their heterogeneous nature currently convolutes the study of this dynamic cell lineage; though, efforts to advance marker analysis and lineage mapping technologies are ongoing. These tools will help elucidate the functional significance of fibroblast-cardiomyocyte interactions in vivo and delineate the dynamic nature of normal and pathological cardiac fibroblasts. Since therapeutic promise lies in understanding the interface between developmental biology and the postnatal injury response, future studies to understand the divergent roles played by cardiac fibroblasts both in utero and following cardiac insult are essential.

Autonomic innervation is an essential component of cardiovascular regulation that is first established from the neural crest (NC) lineage in utero and continues developing postnatally. Although in vitro studies have indicated that SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a signaling factor critical for regulating sympathetic neuron differentiation, this has yet to be shown in the complex in vivo environment of cardiac autonomic innervation. Targeting SHP-2 within postmigratory NC lineages resulted in a fully penetrant mouse model of diminished sympathetic cardiac innervation and concomitant bradycardia. Immunohistochemistry of the sympathetic nerve marker tyrosine hydroxylase revealed a progressive loss of adrenergic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Molecularly, Shp2 cKOs exhibit lineage-specific suppression of activated phospo-ERK1/2 signaling but not of other downstream targets of SHP-2 such as pAKT. Genetic restoration of the phosphorylated-extracellular signalregulated kinase (pERK) deficiency via lineage-specific expression of constitutively active MEK1 was sufficient to rescue the sympathetic innervation deficit and its physiological consequences. These data indicate that SHP-2 signaling specifically through pERK in postmigratory NC lineages is essential for development and maintenance of sympathetic cardiac innervation postnatally.A lthough autonomic innervation of the heart begins in utero, functional neurocardiac coupling continues postnatally. Autonomic imbalance and irregular cardiac innervation density result in deadly consequences such as cardiac arrhythmias, heart failure, and sudden cardiac death (1-4). Although a balance between the sympathetic and parasympathetic arms of the autonomic nervous system is required to regulate heart rate, conduction velocity, and the force of each contraction, sympathetic tone predominates in determining the basal heart rate in the mouse.The sympathetic nervous system arises from the neural crest (NC) lineage. Trunk NC cells delaminate and migrate ventrally through the somites to establish the sympathetic trunk ganglia near the dorsal aorta (5, 6). Postmigration, cross-regulatory transcription factors such as Mash1, Phox2a and 2b, and Gata3 (7-13) are temporarily expressed and drive these NC cells to acquire a neuronal fate and eventually to differentiate into sympathetic neurons expressing both neuron specific β-tubulin (NSβT) and tyrosine hydroxylase (TH; the rate-limiting enzyme in catecholamine synthesis) (14-19). From there, a subset of sympathetic NC cells undergoes a second migration to the cervicothoracic and intrinsic cardiac ganglia to establish populations of sympathetic neurons which contribute to the cardiac plexus or "heart brain" (5,20,21). Recent studies exploring the extensive complexity of autonomic cardiac innervation revealed multiple levels of regulation and interaction between parasympathetic and sympathetic arms of autonomic innervation that converges in the heart brain to contr...