Table 1.

Comparison of FMR1 -related ovarian phenotypes among rodent model systems

	CGGnih [33]	YAC-TG296 [34]	CGGdut [40]	Full mutation/knockout [35]	Rat [36]
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

GC, granulosa cell; LC, luteal cell; LH, luteinizing hormone; n/a, not applicable; PD, postnatal days; PM, premutation; WT, wild type; TC, theca cells; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; Akt, also known as Protein Kinase B (PKB), is a serine/threonine-specific protein kinase; mTOR, mammalian target of rapamycin.