Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway.

A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT+ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.

Thirty Years' History since the Discovery of Pax6: From Central Nervous System Development to Neurodevelopmental Disorders.

Pax6 is a sequence-specific DNA binding transcription factor that positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system (CNS). As indicated by the morphological and functional abnormalities in spontaneous Pax6 mutant rodents, Pax6 plays pivotal roles in various biological processes in the CNS. At the initial stage of CNS development, Pax6 is responsible for brain patterning along the anteroposterior and dorsoventral axes of the telencephalon. Regarding the anteroposterior axis, Pax6 is expressed inversely to Emx2 and Coup-TF1, and Pax6 mutant mice exhibit a rostral shift, resulting in an alteration of the size of certain cortical areas. Pax6 and its downstream genes play important roles in balancing the proliferation and differentiation of neural stem cells. The Pax6 gene was originally identified in mice and humans 30 years ago via genetic analyses of the eye phenotypes. The human PAX6 gene was discovered in patients who suffer from WAGR syndrome (i.e., Wilms tumor, aniridia, genital ridge defects, mental retardation). Mutations of the human PAX6 gene have also been reported to be associated with autism spectrum disorder (ASD) and intellectual disability. Rodents that lack the Pax6 gene exhibit diverse neural phenotypes, which might lead to a better understanding of human pathology and neurodevelopmental disorders. This review describes the expression and function of Pax6 during brain development, and their implications for neuropathology.

Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex.

Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome-interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring's prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring's prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.

Chronic brain histamine depletion in adult mice induced depression-like behaviours and impaired sleep-wake cycle.

Histamine acts as a neurotransmitter to regulate various physiological processes. Brain histamine is synthesized from an essential amino acid histidine in a reaction catalysed by histidine decarboxylase (Hdc). Hdc-positive neurons exist mainly in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project their axons to the entire brain. Recent studies have reported that a chronic decrease in histamine levels in the adult human brain was observed in several neurological disorders. However, it is poorly understood whether lower histamine levels play a causative role in those disorders. In the present study, we induced chronic histamine deficiency in the brains of adult mice to allow direct interpretation of the relationship between an impaired histaminergic nervous system and the resultant phenotype. To induce chronic brain histamine deficiency starting in adulthood, adeno-associated virus expressing Cre recombinase was microinjected into the TMN of Hdc flox mice (cKO mice) at the age of 8 weeks. Immunohistochemical analysis showed expression of Cre recombinase in the TMN of cKO mice. The reduction of histamine contents with the decreased Hdc expression in cKO brain was also confirmed. Behavioural studies revealed that chronic histamine depletion in cKO mice induced depression-like behaviour, decreased locomotor activity in the home cage, and impaired aversive memory. Sleep analysis showed that cKO mice exhibited a decrease in wakefulness and increase in non-rapid eye movement sleep throughout the day. Taken together, this study clearly demonstrates that chronic histamine depletion in the adult mouse brain plays a causative role in brain dysfunction.

Gene tracing analysis reveals the contribution of neural crest-derived cells in pituitary development.

The anterior pituitary originates from the adenohypophyseal placode. Both the preplacode region and neural crest (NC) derive from subdivision of the neural border region, and further individualization of the placode domain is established by a reciprocal interaction between placodal precursors and NC cells (NCCs). It has long been known that NCCs are present in the adenohypophysis as interstitial cells. A recent report demonstrated that NCCs also contribute to the formation of pericytes in the developing pituitary. Here, we attempt to further clarify the role of NCCs in pituitary development using P0-Cre/EGFP reporter mice. Spatiotemporal analyses revealed that GFP-positive NCCs invaded the adenohypophysis in a stepwise manner. The first wave was detected on mouse embryonic day 9.5 (E9.5), when the pituitary primordium begins to be formed by adenohypophyseal placode cells; the second wave occurred on E14.5, when vasculogenesis proceeds from Atwell's recess. Finally, fate tracing of NCCs demonstrated that NC-derived cells in the adenohypophysis terminally differentiate into all hormone-producing cell lineages as well as pericytes. Our data suggest that NCCs contribute to pituitary organogenesis and vasculogenesis in conjunction with placode-derived pituitary stem/progenitor cells.