Sex differences in lower urinary tract biology and physiology

Abstract Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review

Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks.

Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation

Characterization the of Tg64 family.

<p>(a) 3dMD photos of all Tg64 duplication carriers: proband (left), carrier sister (middle), carrier mother (right). (b) Carrier status of Tg64 family members for the gain observed at 19p13.12 (chr19:15051982–15809751; hg19) and sequence variant at <i>TPTE / PTEN2</i> (NM_199261.3:c.1357-3_1357-2delTA). (c) Summary of head circumference measurements and developmental concerns for Tg64 family members.</p

Summary of cases with copy number variants at 19p13.12 in relation to RefSeq genes.

<p>Black bars represent the critical interval breakpoints. Deletions and duplications are presented in red and blue, respectively. Cases are encoded as follows: 1- DECIPHER 257523; 2- Gallant et al., 2011; 3- DECIPHER 285763; 4- DECIPHER 283124; 5- DECIPHER 284366; 6- Engels et al., 2007/Bonaglia et al., 2010; 7- Bonaglia et al., 2010; 8- Van der Aa et al., 2010/DECIPHER 255743; 9- DECIPHER 249355; 10- DECIPHER 249428; 11- Sanders et al., 2011; 12- Tg64.100; 13- Tg64.002; 14- Tg64.001; 15- DECIPHER 265764; 16- Jelsig et al., 2012; 17- DECIPHER 250827; 18- DECIPHER 255839; 19- Kosaki et al., 2011.</p

Chr19p13.12 duplication breakpoints.

<p>Results from an Affy 6.0 SNP array of Tg64.001 reveal a 760 kb duplication at 19p13.12. The top panel displays the log2 ratio of normalized intensity. The middle panel shows the difference of A allele signal and B allele signal. The bottom panel displays a Gaussian smoothed copy number estimate. Intensity values for probes included on the 44k Agilent array used in initial clinical evaluation are overlaid in green ovals.</p

Summary of cytogenetic and clinical findings in cases with overlapping events at 19p13.12.

<p>Summary of cytogenetic and clinical findings in cases with overlapping events at 19p13.12.</p

A subset of genes dysregulated as a result of <i>CYFIP1</i> knockdown show striking similarity to known epilepsy genes, and as such are strong candidate disease genes.

<p>A subset of genes dysregulated as a result of <i>CYFIP1</i> knockdown show striking similarity to known epilepsy genes, and as such are strong candidate disease genes.</p

Genes implicated in schizophrenia and epilepsy, but not conditions unrelated to BP1-2 deletions, are overrepresented among <i>CYFIP1</i> knockdown dysregulated mRNAs.

<p>Genes implicated in schizophrenia and epilepsy, but not conditions unrelated to BP1-2 deletions, are overrepresented among <i>CYFIP1</i> knockdown dysregulated mRNAs.</p

Epilepsy genes dysregulated in response to <i>CYFIP1</i> knockdown are involved in synaptic transmission.

<p>Epilepsy genes dysregulated in response to <i>CYFIP1</i> knockdown are involved in synaptic transmission.</p

<i>CYFIP1</i> knockdown results in dysregulation of hundreds of genes in human neural progenitor cells (NPCs).

<p> (<b>A</b>) RNA-seq and qPCR show that compared to non-silencing control transduced NPC lines (NS, black), cells transduced with an shRNA targeting <i>CYFIP1</i> (<i>CYFIP1</i>^KD, grey and hatched) show a significant reduction in <i>CYFIP1</i> mRNA in lines from three different BP1-2 copy number neutral individuals (C2, red; C4, green; C5, blue, n = 3 per group throughout). P-values for RNA-seq analysis- DESeq2; qPCR- one-tailed Student’s t-test; *p≤ 0.05; ****p≤0.0001. (<b>B</b>) RNA-seq shows that mRNAs for NPC markers are expressed 10 to 100-fold higher than mRNAs for neuronal and glial markers. TPM values are averaged across NS and <i>CYFIP1</i>^KD samples. (<b>C</b>, <b>D</b>) Only a handful of genes are similarly dysregulated in response to <i>CYFIP1</i> knockdown across all three NPC lines evaluated. (<b>E</b>) Unsupervised hierarchical clustering of genes showing nominal differential expression (p<0.05) points to marked between-line differences. (<b>F</b>) RNA-seq and qPCR on mRNA from control and <i>CYFIP1</i>^KD NPCs (<i>CYFIP1</i>^KD RNA-seq, black; <i>CYFIP1</i>^KD qPCR, grey) show reduced levels of genes downregulated in all three cell lines. Abbreviations: <i>CCND1</i>- cyclin D1, <i>GFRA1</i>- GDNF family receptor alpha-1, <i>GPR133</i>- G-protein coupled receptor 133, <i>L1CAM</i>- L1 cell adhesion molecule, <i>PGPEP1</i>- pyroglutamyl-peptidase I, <i>TIPARP</i>- TCDD-inducible poly(ADP-ribose) polymerase.</p