Table 1 Comparison of FMR1 -related ovarian phenotypes among rodent model systems

Genetic background

C57BL/6

FVB/N

C57BL/6 and FVB/n

FVB129P2

Sprague–Dawley

Premutation repeat size

Approximately 130 repeats (variable)

(CGG)₉AGG(CGG)₉AGG(CGG)₇₂

>100 repeats (variable)

n/a

n/a

Expression of WT

FMRP expression:

FMRP expression:

FMRP expression:

n/a

FMRP expression:

• In GCs, LCs

• In GCs and oocytes at all follicle stages

• In GCs of growing follicles (20 weeks)

• In GCs, TCs, stroma of pre-antral follicles

• In oocytes of all ages (high in primordial, primary and early pre-antral follicles)

• Not in interstitial cells

• LCs in older stages

• In oocytes

• Not in interstitial cells

FMR1 mRNA expression:

• In oocyte cytoplasm in primordial follicles (only observed in nucleus in a small fraction of cells)

• In GCs and oocytes at all follicle stages

• Higher levels in ovaries compared with brain

• Not in stromal cells

• Not in interstitial cells

• Weaker in atretic cells

• Levels increased with increasing stage of follicular development

FMR1 mRNA expression:

• Pre-antral and early antral follicles had higher expression than pre-ovulatory follicles

FMRP levels in model

• Reduced FMRP in GCs and LCs

No altered expression measured at 6 to 8 weeks

43% reduced in ovaries at 40 weeks

n/a

• At 7 months, no altered levels in any ovarian cell

• At 7 months, abnormal distribution, higher in nucleus than cytoplasm

FMR1 mRNA levels in model

• Increased at all ages in ovary

Increased levels in ovaries

Increased in ovaries by 4.8-fold at 40 weeks

• Increased in GCs and oocytes (7 months)

Nuclear inclusions

• One seen in 1 oocyte of 1/45 PM mice

Not done

None

• None observed in other ovarian cells

Ubiquitination

• Higher levels in oocytes

Not done

• Animals with > FMRP nuclear distribution had highest number of oocytes with high concentration of ubiquitination

Histopathology

• Grossly normal at 4 months, but 15% smaller

• Reduced uterine weight

• Increased number of follicles by 3 weeks

• Ovarian volume did not change from 4 to 12 months; no correlation with total number of oocytes and corpus lutea (in WT, declined linearly and strong correlation)

• At PD8 and PD25, ovary size did not differ

• Smaller size at 9 and 16 weeks

• Ovaries larger by 3 weeks (by 12 and 18 weeks 22% and 72% larger by mass than controls)

• Interstitial hypertrophy and tubulostromal hypertrophy (7 to 12 months)

• Prominent cysts consistent with corpus lutea development at 18 weeks

• Increase in ovarian cysts (incidence, number and size)

Pattern of follicle counts compared with WT

• Same at 4 months

• At PD25, same number of primordial follicles

• >4 months, fewer follicles

• Number of mature follicles reduced at PD25 and 9 weeks

• All subclasses of follicles were reduced

• Size of primordial pool correlated with number of advancing subclasses

• Reduction of less mature follicle stages but not significant

Corpus luteum characteristics

• Reduced

• Reduced at 9 weeks

• Decline associated with number of advanced follicles

Granulosa cell characteristics

• Antral follicles had 15% fewer GCs

• Appeared with detached GC layer

• Corona of mature follicles was partial or missing leading to premature meiotic progression

Atresia characteristics

• High ratio of atretic follicles to advancing follicles irrespective of estrus cycle

• Strong positive TUNEL in follicles at PD35 to 22 weeks showing an increased number of atretic cells

• Association of atresia rate and repeat number

Fertility characteristic

• Not published, but unpublished work from same group supports a lower fecundity.

• Increased sterility

• Delayed time to first pregnancy

• Reduced number of pups per litter

Hormone profile

Not done

• At 10 to 12 weeks, higher levels of 17β-E2, but similar levels at 16 and 22 weeks

• From 9 to 22 weeks, follicle-stimulating hormone higher and LH lower

Expression of other genes

Not done

• At PD25, 8 and 14 weeks, LH receptor downregulated

• Increased protein levels of Tsc2, Sash1 and mTOR

• Large number of LH-induced ovulation-related genes downregulated at proestrus stage in adults

• Reduced phosphorylated Akt and phosphorylated mTOR, but total levels of Akt and mTOR were not altered

• No alterations in other major known regulators of folliculogenesis