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PubMed1986

Cognate homeo-box loci mapped on homologous human and mouse chromosomes.

The homeotic genes of Drosophila, which regulate pattern formation during larval development, contain a 180-base-pair DNA sequence termed the "homeo-box." Nucleotide sequence comparisons indicate that the homeo-box motif is highly conserved in a variety of motazoan species. As in Drosophila, homeo-box sequences of mammalian species are expressed in a temporal and tissue-specific pattern during embryogenesis. These observations suggest functional homologies between dipteran and mammalian homeo-box gene products. To identify possible relationships between homeo-box genes of mice and humans, we have compared the chromosomal location of homeo-box genes in these species. Using in situ hybridization and somatic cell genetic techniques, we have mapped the chromosome 6-specific murine Hox-1 homolog to the region p14-p21 on human chromosome 7. We have also regionally mapped the murine Hox-3 locus to 15F1-3 and its human cognate to 12q11-q21. These comparative mapping data indicate that a syntenic relationship in mice and humans is maintained for all homeo-box loci examined to date. We suggest these regions represent evolutionarily conserved genomic domains encoding homologous protein products that function in regulating patterns of mammalian development.

Animals↗
PubMed2006

Mechanisms of gonadal morphogenesis are not conserved between chick and mouse.

To understand mechanisms of sex determination, it is important to know the lineage relationships of cells comprising the gonads. For example, in mice, the Y-linked gene Sry triggers differentiation of Sertoli cells from a cell population originating in the coelomic epithelium overlying the nascent gonad that also gives rise to uncharacterised interstitial cells. In contrast, little is known about origins of somatic cell types in the chick testis, where there is no Sry gene and sex determination depends on a ZZ male/ZW female mechanism. To investigate this, we performed fate mapping experiments in ovo, labelling at indifferent stages the coelomic epithelium by electroporation with a lacZ reporter gene and the underlying nephrogenous (or mesonephric) mesenchyme with chemical dyes. After sex differentiation, LacZ-positive cells were exclusively outside testis cords and were 3betaHSD-negative, indicating that the coelomic epithelium contributes only to non-steroidogenic interstitial cells. However, we detected dye-labelled cells both inside and outside the cords. The former were AMH-positive while some of the latter were 3betaHSD-positive, showing that nephrogenous mesenchyme contributes to both Sertoli cells and steroidogenic cells. This is the first demonstration via lineage analysis that steroidogenic cells originate from nephrogenous mesenchyme, but the revelation that Sertoli cells have different origins between chick and mouse suggests that, during evolution, mechanisms of gonad morphogenesis may diverge alongside those of sex determination.

Animals↗
PubMed1983

Genotypic and phenotypic evolution of a murine tumor during its progression in vivo toward metastasis.

To follow the cellular progeny of the multiple-drug-marked benign murine tumor cell line MDW4 during its progression in vivo toward metastatic spread in DBA/2 mice, the following parameters were analyzed: retention of the drug-resistant markers ouabain resistance (OuaR) and thioguanine resistance (ThgR), lectin-resistance pattern (WGAR), and the karyotype of cell populations (and clones derived from these cells) removed at intervals from the solid tumor growing at the site of inoculation, as well as distant metastatic nodules. It was determined that the initially homogeneous inoculum composed of OuaR, ThgR, and WGAR hypotetraploid cells (mode: 68 +/- 2 chromosomes) was gradually overgrown and replaced by a new population of cells that were either OuaR or ouabain-sensitive but that became thioguanine-and lectin-sensitive and hyperploid (mode: 95 +/- 5). Regardless of the composition of the individual drug marker combinations, only cells with high chromosome contents were found to be able to disseminate to distant visceral organs and to rapidly produce metastases upon sc or iv reinjection. The presence of the same number of metacentric chromosomes in metastatic cells as in MDW4 and the coextinction of two recessive drug-resistant markers (WGAR and ThgR) suggested that cells endowed with invasive-metastatic potential represent the product of spontaneous somatic hybridization between the original nonmetastatic MDW4 cells and normal host cells of unknown origin. Such a fusion was followed by more or less extensive chromosome segregation that accounts for the karyotype mosaicism and the occasional drug marker heterogeneity identified in cell populations of metastatic nodules.

Animals↗
PubMed1998

The influence of cell context on the selection pressure for p53 mutation in human cancer.

Although p53 mutation is, overall, by far the most frequent somatic genetic abnormality in human cancer, in some common tumour types, notably carcinoma of breast, it is seen only in a phenotypically-distinct sub-set of cases, often correlated with adverse prognosis. Conventionally, this is viewed as the consequence of random differences in acquired genetic events acting on a common cell. Here we develop a fundamentally different hypothesis, which proposes that the liability of a given tumour to exhibit p53 mutation is predetermined by the nature of its cell of origin and, more specifically, depends on the extent to which wild-type p53 forms a rate-limiting step in the control of proliferative lifespan in that cell. In other words, the phenotype of the cell of origin constrains both tumour phenotype and 'choice' of genetic events. This concept can be extended to tumour progression, where evidence particularly from thyroid tumorigenesis suggests that a switch in differentiation state can play a major causal role in tumour evolution by altering the selection pressure for p53 mutation. Finally, analysis of transformed thyroid cells has also revealed a novel physiological mechanism by which growth suppression by wild-type p53 may be evaded in cell types whose lifespan control is p53-independent.

Animals↗
PubMed1988

The brain of Thylacosmilus atrox. Extinct South American saber-tooth carnivore marsupial.

Two endocasts of the extinct marsupial Thylacosmilus atrox are studied. The specimens were found in outcrops at present considered of Pliocene Age. The followings are the conclusions arrived in the study: 1) The encephalon of Thylacosmilus atrox shows a well developed neocortex, with a deep rhinal fissure and the major marsupial neocortical sulci well observable. The homologies of the sulci was certainly easy in the major part of them, and consequently, functional inferencies were possible. 2) The somatic neocortical area shows certain distinctive characteristics. It appears that the size proportions between the mandibular and maxillary areas is reversed in T. atrox, which appears congruent with the infered function of its peculiar cranial anatomy. 3) The relative brain size of T. atrox is very heigh for a Polyprotodont marsupial being its encephalization quotients and progression indexes at the level of the living Diprotodonta. 4) Thylacosmilus atrox was a very peculiar extinct carnivore marsupial, which at the Late Tertiary in South America reached higher levels of encephalization than the posterior or living representatives of its same Order.

Animals↗
PubMed2005

CD4+ T cell responses to SSX-4 in melanoma patients.

Genes of the synovial sarcoma X breakpoint (SSX) family are expressed in different human tumors, including melanomas, but not in adult somatic tissues. Because of their specific expression at the tumor site, SSX-encoded Ags are potential targets for anticancer immunotherapy. In this study, we have analyzed CD4+ T cell responses directed against the Ag encoded by SSX-4. Upon in vitro stimulation of PBMC from four melanoma patients bearing Ag-expressing tumors with a pool of long peptides spanning the protein sequence, we detected and isolated SSX-4-specific CD4+ T cells recognizing several distinct antigenic sequences, mostly restricted by frequently expressed HLA class II alleles. The majority of the identified sequences were located within the Krüppel-associated box domain in the N-terminal region of the protein, indicating a high potential immunogenicity of this region. Together our data document the existence of CD4+ T cells specific for multiple SSX-4 derived sequences in circulating lymphocytes from melanoma patients and encourage further studies to assess the impact of SSX-4-specific T cell responses on disease evolution in cancer patients.

Adult↗
PubMed1991

Chromosome studies on Dasypus, Euphractus and Cabassous genera (Edentata: Dasypodidae).

The somatic and meiotic chromosomes of twenty specimens of the Dasypodidae were studied. The wild specimens belonged to the genera Cabassous, Euphractus and Dasypus. The karyotype of D. novemcinctus showed a diploid chromosome number of 64, although some variation was observed in one specimen where 2n was 65, due to a supernumerary chromosome, and another had a dimorphic pair. D. septemcinctus also had a diploid chromosome number of 64, and showed two variant types due to pericentric inversions and/or centric fusions. E. sexcinctus and C. unicinctus had diploid chromosome numbers of 58 and 50, respectively. These species did not show variant chromosome types, and this was confirmed in meiotic studies. Analysis of the meiotic epithelium of species of Dasypus including the analysis of the synaptonemal complex in pachytene nuclei, showed similar findings to those commonly reported in mammalian meiosis, especially in relation to pairing and formation of the sex bivalent. The evolutionary implications of the chromosome changes in relation to organic evolution are discussed.

Animals↗
PubMed2001

The six hyaluronidase-like genes in the human and mouse genomes.

The human genome contains six hyaluronidase-like genes. Three genes (HYAL1, HYAL2 and HYAL3) are clustered on chromosome 3p21.3, and another two genes (HYAL4 and PH-20/SPAM1) and one expressed pseudogene (HYALP1) are similarly clustered on chromosome 7q31.3. The extensive homology between the different hyaluronidase genes suggests ancient gene duplication, followed by en masse block duplication, events that occurred before the emergence of modern mammals. Very recently we have found that the mouse genome also has six hyaluronidase-like genes that are also grouped into two clusters of three, in regions syntenic with the human genome. Surprisingly, the mouse ortholog of HYALP1 does not contain any mutations, and unlike its human counterpart may actually encode an active enzyme. Hyal-1 is the only hyaluronidase in mammalian plasma and urine, and is also found at high levels in major organs such as liver, kidney, spleen, and heart. A model is proposed suggesting that Hyal-2 and Hyal-1 are the major mammalian hyaluronidases in somatic tissues, and that they act in concert to degrade high molecular weight hyaluronan to the tetrasaccharide. Twenty-kDa hyaluronan fragments are generated at the cell surface in unique endocytic vesicles resulting from digestion by the glycosylphosphatidyl-inositol-anchored Hyal-2, transported intracellularly by an unknown process, and then further digested by Hyal-1. The two beta-exoglycosidases, beta-glucuronidase and beta-N-acetyl glucosaminidase, remove sugars from reducing termini of hyaluronan oligomers, and supplement the hyaluronidases in the catabolism of hyaluronan.

Amino Acid Sequence↗
PubMed2002

Does hereditary metabolic disease modulate senescence and ageing?

Hereditary metabolic diseases in the context of evolutionary biology elicit interesting questions about ageing and senescence: Will persons successfully treated for inborn errors of metabolism, age and die prematurely because of compromised longevity? Because some unhealthy longevity has its origins in germline and somatic mutational processes, and in an inability to withstand metabolic stress, are there lessons to be learned about senescence from hereditary metabolic disease? Why are ageing, senescence and death necessary for Homo sapiens and how do they happen? These questions form the theme upon which several variations are played during the course of this essay. The theory of the disposable soma recognizes genomic and environmental events, well-seasoned by Chance, as determinants of ageing and senescence. Together, they cause the somatic damage that results in death. Genomics will reveal genes involved in longevity, both healthy and unhealthy. There will be schedules of gene expression behind our life-history traits. As in the field of hereditary metabolic disease, analogous genetic enquiries about ageing can be formulated. For example, how will heterozygotes age? Will association studies in centenarians reveal 'longevity genes'? Will disparate longevity in sib pairs reveal genetic factors? If there are 'ageing' mutations, of what types and with what effects? Will these initiatives lead to healthier longevity? A deeper question yet remains: why has human biology invested so greatly in grandparenthood?

Aging↗
PubMed2004

The interaction between reproductive lifespan and protandry in seasonal breeders.

The timing and duration of reproductive activities are highly variable both at the individual and population level. Understanding how this variation evolved by natural selection is fundamental to understanding many important aspects of an organism's life history, ecology and behaviour. Here, we combine game theoretic principles governing reproductive timing and the evolutionary theory of senescence to study the interaction between protandry (the earlier arrival or emergence of males to breeding areas than females) and senescence in seasonal breeders. Our general model applies to males who are seeking to mate as frequently as possible over a relatively short period, and so is relevant to many organisms including annual insects and semelparous vertebrates. The model predicts that protandry and maximum reproductive lifespans should increase in environments characterized by high survival and by a low competitive cost of maintaining the somatic machinery necessary for survival. In relatively short seasons under these same conditions, seasonal declines in the reproductive lifespans of males of equivalent quality will be evolutionarily stable. However, over a broad range of potential values for daily survival and maintenance cost, reproductive lifespan is expected to be relatively short and constant throughout a large fraction of the season. We applied the model to sockeye (or kokanee) salmon Oncorhynchus nerka and show that pronounced seasonal declines in reproductive lifespan, a distinctive feature of semelparous Oncorhynchus spp., is likely part of a male mating strategy to maximize mating opportunities.

Aging↗
PubMed2001

Late effects in long-term survivors of ALL in childhood: experiences from the SPOG late effects study.

With the use of more intensive regimens including prophylactic CNS treatment, the prognosis of children with ALL has dramatically improved over the last three decades. The aim of this cross-sectional, nationwide study was to comprehensively assess long-term toxicity in ALL survivors, with special attention given to neuropsychological morbidity, and to look for possible differences in cognitive outcome between children having received prophylactic cranial irradiation and those not having received it. Between 1994 and 1996, long-term survivors of ALL were assessed in a multi-center setting according to a standardized protocol which included, besides usual clinical and laboratory investigations, a comprehensive endocrine work-up. Additionally, children having received anthracyclines were checked for possible late cardio-toxicity with echocardiography and ECG. Intellectual performance was evaluated with standardized neuropsychological tests (age-adapted versions of the Wechsler test). One-hundred and fifty patients were eligible for the study. The median age at diagnosis was 5 years and at evaluation 16 years, for a median follow-up of 10 years. Thirty-five patients had cranial irradiation as part of the prophylactic CNS treatment. One-hundred and forty (93%) of the 150 eligible patients were completely evaluated in terms of global long-term toxicity: 117 (83%) long-term survivors had no (n = 61) or only minimal (n = 56) late toxicity; 19 (14%) suffered from moderate impairments; 4 (3%) showed severe somatic or neuropsychological sequelae. Intellectual performance could be assessed in 147 (98%) of the 150 eligible patients. The mean global, verbal and non-verbal IQs (103, 105 and 101 respectively) of the ALL survivors as a group were comparable with those found in the general population. The results of the comparison between children having and those not having received prophylactic cranial irradiation showed: 1) significantly higher scores in chemotherapy-only treated patients, both for the global and the verbal performances; 2) significantly poorer results in specific items of the Wechsler test (short-term verbal memory, arithmetics, concentration/speed of processing) in irradiated children. These findings which show the deleterious role of cranial irradiation correlate well with many other reports found in the literature. However, they could have been influenced by the significantly longer time interval observed between therapy and evaluation in our irradiated patients. Prospective studies are needed to further characterize the potential neuropsychological hazards of chemotherapy and their evolution over time.

Adolescent↗
PubMed1983

Monoclonal anti-VH antibodies recognize a common VH determinant expressed on immunoglobulin heavy chains from various species.

Our previous work using rabbit antibodies to the variable region of MOPC315 myeloma heavy chain (VH) has indicated the existence of framework determinant(s) common to many murine heavy chains. Here we report the characterization of anti-VH monoclonal antibodies (mAb) prepared in an attempt to elucidate the nature of the common VH determinant. We immunized AKR/J mice with a purified VH315 fragment and generated somatic cell hybrids by the fusion of the immune AKR/J splenocytes with the NS1 myeloma cells. Thirty-seven common anti-VH and 57 subgroup VHI-specific hybridomas have been established and characterized. Whereas the anti-subgroup mAb seemed to react with a determinant unique to the MOPC315 (mouse VHI) subgroup, all the anti-VH mAb reacted with myeloma heavy chains of different VH subgroups, class and allotypes. Antibody competition studies revealed that the VH subgroup determinants are distinct from the common VH determinants and that both were also recognized by the rabbit polyclonal antibodies. The common VH determinants were found to be "hidden" determinants on intact immunoglobulin molecules being exposed only on isolated heavy chains. Furthermore, they are sequential determinants since they are preserved on fully denatured heavy chains. The common VH determinants are shared by immunoglobulins of a wide range of vertebrates from amphibia to man and thus represent antigenic structures which were highly conserved throughout evolution.

Animals↗
PubMed2005

Silencing of the mammalian X chromosome.

Mammalian X chromosome inactivation is one of the most striking examples of epigenetic gene regulation. Early in development one of the pair of approximately 160-Mb X chromosomes is chosen to be silenced, and this silencing is then stably inherited through subsequent somatic cell divisions. Recent advances have revealed many of the chromatin changes that underlie this stable silencing of an entire chromosome. The key initiator of these changes is a functional RNA, XIST, which is transcribed from, and associates with, the inactive X chromosome, although the mechanism of association with the inactive X and recruitment of facultative heterochromatin remain to be elucidated. This review describes the unique evolutionary history and resulting genomic structure of the X chromosome as well as the current understanding of the factors and events involved in silencing an X chromosome in mammals.

Animals↗
PubMed2026

Acute leukemia therapy at a crossroads: from conventional chemotherapy to the era of precision medicine.

Since the discovery of cytotoxic agents in the mid-20th century, acute leukemia has consistently served as a model for oncology research. As the Human Genome Project and subsequent genomic profiling elucidated the landscape of somatic mutations and cytogenetic aberrations driving leukemogenesis, the development of molecularly targeted therapies has dramatically accelerated, yielding significant improvements in patient outcomes. In acute myeloid leukemia (AML), the emergence of selective inhibitors targeting high-frequency alterations such as FLT3, NPM1, and IDH1/2 has redefined the standard of care, demonstrating superior efficacy when combined with conventional intensive chemotherapy or hypomethylating agents. Simultaneously, for acute lymphoblastic leukemia (ALL), in addition to the significant improvements achieved by tyrosine kinase inhibitors (TKIs) for BCR-ABL-positive ALL, the advent of CD19- or CD22-targeted monoclonal antibodies and CAR-T cell therapies has marked an epoch-making milestone, representing a major paradigm shift in the management of relapsed or refractory cases. Bridging these two distinct lineages, menin inhibitors have emerged as a novel class of agents targeting a common pathogenic mechanism in KMT2A-rearranged AML/ALL and NPM1-mutated AML, exhibiting promising antileukemic activity across these subtypes. In this review, we describe the evolution of leukemia therapy-highlighting historical trajectory across AML, APL, and ALL from uniform cytotoxic chemotherapy to molecularly targeted agents, antibody-based therapies, and chemo-free paradigms, while outlining future perspectives for precision hematology.

Acute lymphoblastic leukemia↗
PubMed2026

Mobile elements in pituitary neuroendocrine tumors: integrative evidence and future directions.

Mobile genetic elements (MGEs), including LINE-1 retrotransposons, Alu and SVA elements, and human endogenous retroviruses (HERVs), constitute nearly half of the human genome and are increasingly understood to influence multiple dimensions of cancer evolution. Yet, pituitary neuroendocrine tumors (PitNETs) remain almost absent from mobilome research, despite exhibiting genomic and epigenetic contexts permissive to retroelement activation. In this review, we synthesize current evidence linking MGEs to PitNET biology and delineate unresolved but testable mechanisms. Structural genomic studies demonstrate that Alu-mediated non-allelic homologous recombination contributes to germline mutagenesis in MEN1 and AIP, reinforcing the notion that repetitive DNA architecture shapes PitNET predisposition. Transcriptomic analyses reveal global derepression of transposable elements and LINE-1 hypomethylation in subsets of tumors, while mechanistic connections to chromatin instability emerge from recurrent ATRX/DAXX deficiency and TP53 inactivation, both established repressors of retroelements. Furthermore, the retrocopy-derived long non-coding RNA RPSAP52 exemplifies how mobilome-origin transcripts can be co-opted as oncogenic regulators in PitNETs, acting through HMGA2-dependent proliferative networks. Preliminary data also suggest endogenous retroviral activation, with consistent upregulation of HERV envelope genes across distinct tumor subtypes. Nevertheless, no study has yet systematically mapped somatic mobile-element insertions (MEIs), quantified LINE-1 protein activity, or profiled HERV expression at locus resolution in PitNETs. Mobilome biology represents a tractable and conceptually rich frontier with diagnostic, prognostic, and therapeutic potential in pituitary tumorigenesis.

Humans↗
PubMed1994

Consistent loss of the D5S89 locus mapping telomeric to the interleukin gene cluster and centromeric to EGR-1 in patients with 5q- chromosome.

Interstitial deletions of the long arm of chromosome 5 are common in a number of disorders of leukemic and preleukemic myeloid disorders. Although the limits of these deletions vary among patients, a region of cytogenetic overlap that includes band 5q31 is deleted consistently, suggesting loss of 5q31 loci critical for normal myeloid differentiation and leukemogenesis. An anonymous genomic DNA segment D5S89, previously mapped to 5q21-31, detects consistent loss of alleles in cases showing the 5q- chromosome at presentation or relapse. Analysis of a panel of natural-deletion somatic-cell hybrids in conjunction with irradiation hybrids containing fragments of human chromosome 5q shows that the D5S89 locus is telomeric to the interleukin (IL) genes (IL-3, IL-4, IL-5, IL-9, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) and interferon response factor-1 (IRF-1) gene and centromeric to the early response transcription factor (early growth response gene-1 [EGR-1]) on 5q31. To further define the principal region of loss, we have isolated and characterized yeast artificial chromosomes (YACs) spanning D5S89. The presence of several CpG islands within the 300-kb YAC is suggestive of multiple transcription units. However, IL-4, IL-5, IRF-1, IL-3, GM-CSF, and EGR-1 genes were not detected in the YAC clone spanning D5S89, implying that none of these genes are in the vicinity of the D5S89 marker. Further characterization of these YACs should facilitate the isolation of novel candidate genes that may play a role in the evolution of the abnormal phenotype associated with 5q- chromosome.

Adult↗
PubMed2000

Aneuploidy precedes and segregates with chemical carcinogenesis.

A century ago, Boveri proposed that cancer is caused by aneuploidy, an abnormal balance of chromosomes, because aneuploidy correlates with cancer and because experimental aneuploidy generates "pathological" phenotypes. Half a century later, when cancers were found to be nonclonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result, aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer. However, we have recently proposed a two-stage mechanism of carcinogenesis that resolves the discrepancy between clonal mutation and nonclonal karyotypes. The proposal is as follows: in stage 1, a carcinogen "initiates" carcinogenesis by generating a preneoplastic aneuploidy; in stage 2, aneuploidy causes asymmetric mitosis because it biases balance-sensitive spindle and chromosomal proteins and alters centrosomes both numerically and structurally (in proportion to the degree of aneuploidy). Therefore, the karyotype of an initiated cell evolves autocatalytically, generating ever-new chromosome combinations, including neoplastic ones. Accordingly, the heterogeneous karyotypes of "clonal" cancers are an inevitable consequence of the karyotypic instability of aneuploid cells. The notorious long latent periods, of months to decades, from carcinogen to carcinogenesis, would reflect the low probability of evolving by chance karyotypes that compete favorably with normal cells, in principle analagous to natural evolution. Here, we have confirmed experimentally five predictions of the aneuploidy hypothesis: (1) the carcinogens dimethylbenzanthracene and cytosine arabinoside induced aneuploidy in a fraction of treated Chinese hamster embryo cells; (2) aneuploidy preceded malignant transformation; (3) transformation of carcinogen-treated cells occurred only months after carcinogen treatment, i.e., autocatalytically; (4) preneoplastic aneuploidy segregated with malignant transformation in vitro and with 14 of 14 tumors in animals; and (5) karyotypes of tumors were heterogeneous. We conclude that, with the carcinogens studied, aneuploidy precedes cancer and is necessary for carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

Male germ cell gene expression.

Formation of the male gamete occurs in sequential mitotic, meiotic, and postmeiotic phases. Many germ cell-specific transcripts are produced during this process. Their expression is developmentally regulated and stage specific. Some of these transcripts are product of genes that are male germ cell-specific homologs of genes expressed in somatic cells, while some are expressed from unique genes unlike any others in the genome. Others are alternate transcripts derived from the same gene as transcripts in somatic cells but differing from them in size and/or overall sequence. They are generated during gene expression by using promoters and transcription factors that activate transcription at different start sites upstream or downstream of the usual site, by incorporation of alternate exons, by germ cell-specific splicing events, and by using alternate initiation sites for polyadenylation. Male germ cell development consists of an assortment of unique processes, including meiosis, genetic recombination, haploid gene expression, formation of the acrosome and flagellum, and remodeling and condensation of the chromatin. These processes are intricate, highly ordered, and require novel gene products and a precise and well-coordinated program of gene expression to occur. The regulation of gene expression in male germ cells occurs at three levels: intrinsic, interactive, and extrinsic. A highly conserved genetic program "intrinsic" to germ cells determines the sequence of events that underlies germ cell development. This has been underscored by recent studies showing that meiosis involves many genes that have been conserved during evolution from yeast to man. During meiosis and other processes unique to germ cells, the intrinsic program determines which genes are utilized and when they are expressed. In the postmeiotic phase, it coordinates the expression of genes whose products are responsible for constructing the sperm. The process of spermatogenesis occurs in overlapping waves, with cohorts of germ cells developing in synchrony. The intrinsic program operating within a particular germ cell requires information from and provides information to neighboring cells to achieve this coordination. Sertoli cells are crucial for this "interactive" process as well as for providing essential support for germ cell proliferation and progression through the phases of development. The interactive level of regulation is dependent on "extrinsic" influences, primarily testosterone and follicle-stimulating hormone (FSH). Studies during the last 4 years have established that FSH is not essential for germ cell development but instead serves an important supportive role for this process. While testosterone is essential for maintenance of spermatogenesis, it acts on Sertoli cells and peritubular cells and has indirect effects on germ cells. The extrinsic and interactive processes are extremely important for establishing and maintaining an optimum environment within which gametogenesis occurs. Nevertheless, an intrinsic evolutionarily conserved genetic program regulates male germ cell gene expression and development.

Animals↗