Blanche Capel

Overview:

In mammals, the primary step in male sex determination is the initiation of testis development in the bipotential gonad primordium. This step depends on the Y-linked male sex-determining gene, Sry. Expression of Sry in the XY gonad, or as a transgene in an XX gonad, leads to the differentiation of Sertoli cells. Failures in Sertoli cell differentiation in the XY gonad result in sex reversal and ovary formation. In addition to Sertoli cell differentiation, we are studying the signaling pathways between Sry expression and early steps in testis organogenesis using mouse as a model system. Using genetic and cell biology approaches, we determined the origin of several key cell types of the testis. We also identified two pathways, proliferation and cell migration, that are controlled by Sry and lead to the architectural patterning of the testis. Currently we are investigating the novel hypothesis that reciprocal signals between the vasculature and Sertoli cells are involved in patterning testis cords. Testis organogenesis is an ideal model system to study the integration of vasculature during development of organ structure. In addition, we are investigating critical signals between Sertoli cells and germ cells during testis cord formation. Defects in these signals result in teratomas and gonadal blastomas, common neoplasias in young boys. Experimental approaches include the use of molecular and biochemical techniques, mutant mice, transgenics, organ culture assays, differential screens, immunocytochemistry imaging techniques, and classic mouse genetics.

Positions:

James B. Duke Distinguished Professor of Cell Biology

Cell Biology
School of Medicine

Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

Ph.D. 1989

University of Pennsylvania

Grants:

Identification of a Genetic Pathway Linking Temperature with Epigenetic Control of Gonad Determination in T. scripta

Administered By
Cell Biology
Awarded By
National Science Foundation
Role
Principal Investigator
Start Date
End Date

Defining Mechanisms of Ovarian Rescue

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Opposing Pathways in Mammalian Sex Determination

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Opposing Pathways in Mammalian Sex Determination

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

DND1 Mediated Posttranscriptional Regulation in Murine Prospermatogonia During G1/G0 Arrest

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Temperature-dependent sex determination is mediated by pSTAT3 repression of Kdm6b.

In many reptiles, including the red-eared slider turtle Trachemys scripta elegans (T. scripta), sex is determined by ambient temperature during embryogenesis. We previously showed that the epigenetic regulator Kdm6b is elevated at the male-producing temperature and essential to activate the male pathway. In this work, we established a causal link between temperature and transcriptional regulation of Kdm6b We show that signal transducer and activator of transcription 3 (STAT3) is phosphorylated at the warmer, female-producing temperature, binds the Kdm6b locus, and represses Kdm6b transcription, blocking the male pathway. Influx of Ca2+, a mediator of STAT3 phosphorylation, is elevated at the female temperature and acts as a temperature-sensitive regulator of STAT3 activation.
Authors
Weber, C; Zhou, Y; Lee, JG; Looger, LL; Qian, G; Ge, C; Capel, B
MLA Citation
Weber, Ceri, et al. “Temperature-dependent sex determination is mediated by pSTAT3 repression of Kdm6b.Science, vol. 368, no. 6488, Apr. 2020, pp. 303–06. Pubmed, doi:10.1126/science.aaz4165.
URI
https://scholars.duke.edu/individual/pub1437992
PMID
32299951
Source
pubmed
Published In
Science
Volume
368
Published Date
Start Page
303
End Page
306
DOI
10.1126/science.aaz4165

Intravital imaging of mouse embryos.

Embryonic development is a complex process that is unamenable to direct observation. In this study, we implanted a window to the mouse uterus to visualize the developing embryo from embryonic day 9.5 to birth. This removable intravital window allowed manipulation and high-resolution imaging. In live mouse embryos, we observed transient neurotransmission and early vascularization of neural crest cell (NCC)-derived perivascular cells in the brain, autophagy in the retina, viral gene delivery, and chemical diffusion through the placenta. We combined the imaging window with in utero electroporation to label and track cell division and movement within embryos and observed that clusters of mouse NCC-derived cells expanded in interspecies chimeras, whereas adjacent human donor NCC-derived cells shrank. This technique can be combined with various tissue manipulation and microscopy methods to study the processes of development at unprecedented spatiotemporal resolution.
Authors
Huang, Q; Cohen, MA; Alsina, FC; Devlin, G; Garrett, A; McKey, J; Havlik, P; Rakhilin, N; Wang, E; Xiang, K; Mathews, P; Wang, L; Bock, C; Ruthig, V; Wang, Y; Negrete, M; Wong, CW; Murthy, PKL; Zhang, S; Daniel, AR; Kirsch, DG; Kang, Y; Capel, B; Asokan, A; Silver, DL; Jaenisch, R; Shen, X
MLA Citation
Huang, Qiang, et al. “Intravital imaging of mouse embryos.Science, vol. 368, no. 6487, Apr. 2020, pp. 181–86. Pubmed, doi:10.1126/science.aba0210.
URI
https://scholars.duke.edu/individual/pub1436476
PMID
32273467
Source
pubmed
Published In
Science
Volume
368
Published Date
Start Page
181
End Page
186
DOI
10.1126/science.aba0210

Combined iDISCO and CUBIC tissue clearing and lightsheet microscopy for in toto analysis of the adult mouse ovary†.

At any given time, the ovary contains a number of follicles in distinct growth stages, each with a set of identifying characteristics. Although follicle counting and staging using histological stains on paraffin-embedded ovary sections has been the gold standard in assessing ovarian health in fertility studies, the final counts rely on extrapolation factors that diverge greatly among studies. These methods also limit our ability to investigate spatial aspects of ovary organization. Recent advances in optical tissue clearing and lightsheet microscopy have permitted comprehensive analysis of intact tissues. In this study, we set out to determine the best clearing and imaging methods to generate 3D images of the complete adult mouse ovary that could be used for accurate assessments of ovarian follicles. We found that a combination of iDISCO and CUBIC was the best method to clear the immunostained ovary. Using lightsheet microscopy, we generated 3D images of the intact ovary and performed qualitative assessments of follicles at all stages of development. This study is an important step toward developing quantitative computational models that allow rapid and accurate assessments of growing and quiescent primordial follicles, and to investigate the integrity of extrinsic ovarian components including vascular and neuronal networks.
Authors
McKey, J; Cameron, LA; Lewis, D; Batchvarov, IS; Capel, B
MLA Citation
McKey, Jennifer, et al. “Combined iDISCO and CUBIC tissue clearing and lightsheet microscopy for in toto analysis of the adult mouse ovary†.Biology of Reproduction, vol. 102, no. 5, Apr. 2020, pp. 1080–89. Epmc, doi:10.1093/biolre/ioaa012.
URI
https://scholars.duke.edu/individual/pub1428103
PMID
31965156
Source
epmc
Published In
Biology of Reproduction
Volume
102
Published Date
Start Page
1080
End Page
1089
DOI
10.1093/biolre/ioaa012

Sertoli cell ablation and replacement of the spermatogonial niche in mouse.

Spermatogonia, which produce sperm throughout the male lifetime, are regulated inside a niche composed of Sertoli cells, and other testis cell types. Defects in Sertoli cells often lead to infertility, but replacement of defective cells has been limited by the inability to deplete the existing population. Here, we use an FDA-approved non-toxic drug, benzalkonium chloride (BC), to deplete testis cell types in vivo. Four days after BC administration, Sertoli cells are preferentially depleted, and can be replaced to promote spermatogenesis from surviving (host) spermatogonia. Seven days after BC treatment, multiple cell types can be engrafted from fresh or cryopreserved testicular cells, leading to complete spermatogenesis from donor cells. These methods will be valuable for investigation of niche-supporting cell interactions, have the potential to lead to a therapy for idiopathic male infertility in the clinic, and could open the door to production of sperm from other species in the mouse.
Authors
Yokonishi, T; McKey, J; Ide, S; Capel, B
MLA Citation
Yokonishi, Tetsuhiro, et al. “Sertoli cell ablation and replacement of the spermatogonial niche in mouse.Nat Commun, vol. 11, no. 1, Jan. 2020, p. 40. Pubmed, doi:10.1038/s41467-019-13879-8.
URI
https://scholars.duke.edu/individual/pub1426954
PMID
31896751
Source
pubmed
Published In
Nature Communications
Volume
11
Published Date
Start Page
40
DOI
10.1038/s41467-019-13879-8

WOMEN IN REPRODUCTIVE SCIENCE: To be or not to be a testis.

Work that established the testis as the driver of male development, and the Y chromosome as the bearer of the male-determining gene, established a working model, and set the stage for the molecular age of mammalian sex determination. The discovery and characterization of Sry/SRY at the top of the hierarchy in mammals launched the field in two major directions. The first was to identify the downstream transcription factors and other molecular players that drive the bifurcation of Sertoli and granulosa cell differentiation. The second major direction was to understand organogenesis of the early bipotential gonad, and how divergence of its two distinct morphogenetic pathways (testis and ovary) is regulated at the cellular level. This review will summarize the early discoveries soon after Sry was identified and focus on my study of the gonad as a model of organogenesis.
Authors
MLA Citation
Capel, Blanche. “WOMEN IN REPRODUCTIVE SCIENCE: To be or not to be a testis.Reproduction, vol. 158, no. 6, Dec. 2019, pp. F101–11. Pubmed, doi:10.1530/REP-19-0151.
URI
https://scholars.duke.edu/individual/pub1396204
PMID
31265995
Source
pubmed
Published In
Reproduction
Volume
158
Published Date
Start Page
F101
End Page
F111
DOI
10.1530/REP-19-0151