Table 3.

Mouse models of CUL7 and Fbw8, as well as genes of function in the IGF-1/IRS1 pathways

Gene	Model	Phenotype/observations		Ref.
CUL7	KO	fetal growth retardation in later gestational stages (>E12.5) pulmonary anomalies (atelectic lungs, reduced alveolar space)	100% of homozygous offspring died at birth due to respiratory failure and cyanosis dermal and hypodermal hemorrhages in the lower hip	6
		Placenta:
		reduced size in later gestational stages (>E12.5) abnormal spongiotrophoblast development: smaller decidua and spongiotrophoblast layer, fewer secondary trophoblast giant cells	•smaller materal vessel area in the labyrinth layer
		Mouse embryonic fibroblasts: reduced proliferation rate in culture
FBW8	KO	• fetal growth retardation in later gestational stages (>E12.5)• 70% of Fbw8−/− offspring died at birth of unknown cause, 30% survived but remain smaller throughout adulthood	•no hemorrhages	7, 37
		Placenta:
		reduced size in later gestational stages (>E12.5) abnormal spongiotrophoblast layer, decidua and trophoblast giant cells not affected	•smaller maternal vessel area in the labyrinth layer
		Mouse embryonic fibroblasts: reduced proliferation rate in cell culture
IGF-1R	KO	100% of homozygous offspring died at birth due to respiratory failure and cyanosis; size and weight at birth <45% of wild type generalized organ hypoplasia (including the muscles and skin), anomalies of the nervous system; delayed ossification placental development not affected*		45
IGF-1	KO	>95% of homozygous offspring die at birth due to respiratory failure and cyanosis; size and weight at birth <60% of wild type <5% of IGF-1−/− mice survived birth, but remained smaller throughout life with abnormal development of muscle, reproductive organs (infertility), ossification and skin. placental development not affected*		43–45
IRS-1	KO	•growth retardation of the fetus in later gestational stages (>E15.5), remain 50 60% smaller throughout adulthood.		46–47
		•no organ abnormalities, fertile	•insulin resistant
IGFBP-1	TG	reduced body size and weight generalized organ hypoplasia with exception of brain and spleen	•fasting hyperglycemia	63
IGFBP-2	TG	reduced body size and weight	•fasting hypoglycemia	64

Abbreviations: KO = knockout; TG = transgenic mouse model; IGF-1R = IGF-1 receptor.

^*despite mice deleted of IGF-1 or IGF-1R revealed no significant changes in placental development, emerging evidence points to a critical role of the IGF system in this process throughout gestation (reviewed in ref. 77). Placenta weight was positively correlated with cord blood level of IGF-1 and -2,⁷⁸,⁷⁹ and human placenta explant studies demonstrated a key role of IGF-1 and -2 in promoting cytotrophoblast proliferation and differentiation to synzytiotrophblast cells.⁸⁰